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CN1430600A - 7-and 9-carbamate, urea, thiourea, thiocarbamate and heteroaryl-amino substituted tetracycline compounds - Google Patents

7-and 9-carbamate, urea, thiourea, thiocarbamate and heteroaryl-amino substituted tetracycline compounds Download PDF

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Publication number
CN1430600A
CN1430600A CN01810132A CN01810132A CN1430600A CN 1430600 A CN1430600 A CN 1430600A CN 01810132 A CN01810132 A CN 01810132A CN 01810132 A CN01810132 A CN 01810132A CN 1430600 A CN1430600 A CN 1430600A
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alkyl
compound
vibravenos
amino
hydrogen
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M·L·内尔森
S·B·莱维
R·弗雷彻特
T·E·鲍泽
M·Y·伊斯迈尔
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Paratek Pharmaceuticals Inc
Tufts University
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Paratek Pharmaceuticals Inc
Tufts University
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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    • C07C271/30—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
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    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
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    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

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Abstract

Substituted tetracycline compounds, methods of synthesis, and methods of use are discussed. Tetracyclines useful for treating tetracycline related disorders are also discussed. Intermediates useful for synthesizing other tetracycline compounds are also included.

Description

The tetracycline compound that 7-and 9-carbamate, urea, thiocarbamide, thiocarbamate and heteroaryl-amino replace
Related application
The application requires the U.S. Provisional Application 60/XXX of submission on March 29 calendar year 2001, and XXX, exercise question are " tetracycline compound that 7-and 9-carbamate, urea, thiocarbamide, thiocarbamate and heteroaryl-amino replace "; The U.S. Provisional Application of submitting on March 31st, 2000 number 60/193,972, exercise question is the U.S. Provisional Application number 60/193 of " tetracycline compound that synthetic 7-and 9-replace and the method for reactive intermediate " and submission on March 31st, 2000,879, exercise question is the right of priority of " tetracycline compound that 9-replaces ".The full content of all aforementioned application is attached to herein by reference.
Background of the present invention
The exploitation of tetracycline antibiotic is the direct result that the earth samples of many local collections from the world is carried out screening system in order to prove microorganism can produce the composition of sterilization and/or system bacterium.First of these new compounds is to propose the name with Uromycin (duomycin) in 1948.After 2 years, obtained oxytetracycline (terramycin).The 3rd member's tsiklomitsin of the similarity that the illustrating of the chemical structure of these compounds confirms them and this group of producing for nineteen fifty-two provides analysis foundation.A new family of tetracycline compound is in 1957 preparations and to become the public 1967 obtainable, the methyl group that the ring that this compound does not exist in tsiklomitsin early adheres to.
Research recently makes great efforts to have concentrated on exploitation effective new tetracycline antibiotic composition under treatment condition that changes and route of administration.Also studying new tetracycline analogue, described analogue can provide curative effect or the better therapeutic that equates with the tetracycline compound of introducing the earliest always.Example comprises United States Patent (USP) 3,957,980,3,674,859,2,980,584,2,990,331,3,062,717,3,557,280,4,018,889,4,024,272,4,126,680,3,454,697 and 3,165,531.These patents are the representatives in medical active tsiklomitsin and the tetracycline analogue range of compositions.
From history, after initial exploitation and introducing, find that described tetracyclines to suppressing Rickettsiae, many Gram-positives and gram negative bacterium and causing lymphogranuloma venereum, comprises that the pathogenic factor (agents) of conjunctivitis and psittacosis is very effective on pharmacology.Therefore, tsiklomitsin is widely known by the people as " wide spectrum " microbiotic.Along with their in vitro anti-microbial activity, the validity of experimental infection and the continuous establishment of pharmacological property, tsiklomitsin is widely used for therapeutic purpose rapidly as a class medicine.Yet tsiklomitsin is widely used in serious and slight two class illness and diseases, thereby directly causes occurring these antibiotic resistances, even (for example streptococcus pneumoniae and salmonella) occur in hypersusceptible commensalism and pathogen species.The organic appearance of anti-tsiklomitsin has caused using tsiklomitsin and tetracycline analogue composition generally to reduce as antibiotic selection.
The present invention's general introduction
The present invention relates to, relate to substituted tetracycline compound and its pharmacy acceptable salt of formula (I) to small part:
Figure A0181013200221
Wherein:
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, heteroaryl amino or NR 9cC (=Z ') ZR 9a
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 9dAnd R 9eCan be connected to form a ring;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 7dAnd R 7eCan be connected to form a ring; Condition is to work as R 7During for dialkyl amido or hydrogen, R 9Be not hydrogen.
The present invention also relates to, relate to the method for the tsiklomitsin responsive state for the treatment of the patient to small part.This method comprises the substituted tetracycline compound that gives a kind of formula of described patient (I).
In another embodiment, the present invention includes the substituted tetracycline compound that contains the formula (I) for the treatment of significant quantity and the medicinal compositions of pharmaceutically acceptable carrier.
In another embodiment, the present invention relates to the method for the tetracycline compound of synthetic 7-and/or 9-replacement.This method is included under the condition of nitrocycline compound formation tetracycline compound is contacted with a kind of nitrating agent, this nitrocycline compound is contacted with a kind of hydrogenant agent, and this amino tetracycline compound is contacted with a kind of amino-reactive substrate, so that form the tetracycline compound of 9-or 7-replacement.
The present invention also relates to, relate to the method for the tetracycline compound that the 7-of synthesis type (I) and/or 9-replace to small part, promptly by under suitable condition, a kind of reactive intermediate is contacted with suitable reagent, so that form the substituted tetracycline compound of formula (I).
Reactive intermediate, wherein said reactive intermediate and its pharmacy acceptable salt have following formula: Wherein:
X is CHC (R 13Y ' Y), CHR 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 7Be hydrogen, dialkyl amido, thiocarbamide, diazonium salt, thiocarboxamide or nitro;
R 9Be hydrogen, thiocarbamide, diazonium salt, thiocarboxamide or nitro; Condition is to work as R 7During for dialkyl amido or hydrogen, R 9Be not hydrogen. The present invention describes in detail
The present invention relates to, relate to tsiklomitsin urea, thiocarbamide, carbamate, thiocarbamate, amino-thiazolyl-base and the amino-heteroaryl compound of new 7-and 9-replacement to small part.Can be with the many tetracycline compounds of these compounds for treating-reactive disorder state, as infectation of bacteria and tumour, and other known application of tetracycline compound, modify as tsiklomitsin flow retarding agent (efflux blockers) and genetic expression.
In one embodiment, the present invention includes the tetracycline compound that 7-and 9-replace.The tetracycline compound of preferred described replacement and pharmacy acceptable salt thereof have formula (I): Wherein:
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, heteroaryl amino or NR 9cC (=Z ') ZR 9a
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 9dAnd R 9eCan be connected to form a ring;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 7dAnd R 7eCan be connected to form a ring, condition is to work as R 7During for dialkyl amido or hydrogen, R 9Be not hydrogen.
Described term " tetracycline compound " comprises many compounds with the ring structure that is similar to tsiklomitsin.The example of tetracycline compound comprises: tsiklomitsin, duomycin, terramycin, demecycline, methacycline, Sancycline, Vibravenos and Minocycline HCl.Also comprise derivative and analogue that other contains similar four ring structures.Table 1 has been described tsiklomitsin and seven known tetracycline derivants.In one embodiment, term " unsubstituted tetracycline compound " comprises wherein R 7Be not NR 7cC (=W ') WR 7aBe not heteroaryl-amino and R wherein yet 9Be not that heteroaryl-amino is not NR yet 9cC (=Z ') ZR 9aTetracycline compound.
Table I
Term " tetracycline compound of replacement " is included in the tetracycline compound that there is replacement 7-or 9-position.In one embodiment, the replacement on 7-or 9-position has improved this substituted tetracycline compound and has fulfiled the ability of its expectation function.In one embodiment, the tetracycline compound that replaces of 9-is that the Minocycline HCl that replaces of 9-is (as R wherein 4And R 4 'Be methyl, R 5Be hydrogen, R 7Be dimethylamino, and X is CR 6R 6 ', R wherein 6And R 6 'Be hydrogen atom); The terramycin that 7-or 9-replace is (as R wherein 4And R 4 'Be methyl, R 5Be hydroxyl, X is CR 6R 6 ', R 6Be methyl R 6 'Be hydrogen); Or the Sancycline that replaces of 7-or 9-(R wherein 4And R 4 'Be methyl, R 5Be hydroxyl, X is CR 6R 6 ', R 6And R 6 'Be hydrogen atom).In another embodiment, R 5Can be for the oh group of protection, as the prodrug part.For example, the example of prodrug part comprises acyl ester and propionic ester.In certain embodiments, described prodrug partly is aroyl, alkanoyl or alkane aroyl and in vivo can not cracking or be cracked into oh group.In one embodiment, R 2 ', R 3, R 8, R 10, R 11And R 12Each is a hydrogen.In certain embodiments of the invention, the tetracycline compound of term replacement comprises wherein R 7Or R 9At least one is heteroaryl-amino, NR 7cC (=W ') WR 7a, or NR 9cC (=Z ') ZR 9aTetracycline compound.
In one embodiment, term " tetracycline compound that 9-replaces " comprises wherein R 9Be amino-heteroaryl or NR 9cC (=Z ') ZR 9aCompound.In another embodiment, R 9cBe hydrogen.In another, Z ' is oxygen or sulphur.In one embodiment, Z is oxygen or NR 9b, R wherein 9bBe hydrogen.In another embodiment, R 9aCan be hydrophobic.R 9aAlso can be alkyl, alkenyl (as vinyl, propenyl, butenyl etc.), alkynyl, aryl (as phenyl, heteroaryl etc.), aralkyl or many rings (for example poly-ring is as steroid base (steroidyl), as cholesteryl (chlolesteroidyl)).
In one embodiment, R 9aFor replace or unsubstituted alkyl (as methyl, ethyl, the tertiary butyl, normal-butyl, isobutyl-or n-pentyl).Possible substituent example includes but not limited to alkyl; alkenyl; halogen; hydroxyl; alkoxyl group; alkyl carbonyl oxy; alkoxy carbonyl; aryl-carbonyl oxygen; alkoxycarbonyl amino; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkyl amino-carbonyl; aralkyl; aminocarboxyl; the alkenyl amino carbonyl; alkyl-carbonyl; aryl carbonyl; aminoalkyl group; aromatic alkyl carbonyl; alkenyl carbonyl; alkoxy carbonyl; silyl; aminocarboxyl; the alkylthio carbonyl; phosphoric acid ester; aralkyl; phosphonate group (phosphonato); phosphinato; cyano group; amino; acyl amino; amido; imino-; sulfydryl; alkylthio; sulfuric ester; arylthio; carbothioic acid ester; alkyl sulphinyl; sulfonic group (sulfonato); sulfamyl; sulfonamido; nitro; cyano group; azido-; heterocyclic radical; alkaryl; aryl and heteroaryl.In certain embodiments, described substituting group is alkoxy carbonyl, amino, aryl carbonyl, halogen, hydroxyl, alkylamino, alkoxyl group or aryl.In certain embodiments, described substituting group is halogen (as bromine, chlorine, iodine, a fluorine).
In the another one embodiment, R 9aAt least comprise an aromatic yl group, as heteroaryl, phenyl, naphthyl, fluorenes etc.Fluorenes is the part of following formula:
Figure A0181013200291
In one embodiment, R 9aBe aryl, as that replace or unsubstituted phenyl.Substituent example comprises; but be not limited to; alkyl (as; unsubstituted alkyl such as methyl, ethyl, propyl group, butyl, or the chloromethyl that for example replaces, dichloromethyl, perchloro-methyl, methyl fluoride, difluoromethyl, perfluoro-methyl etc.), alkenyl, alkynyl, aryl, alkoxyl group (as methoxyl group, oxyethyl group, propoxy-etc.), aryloxy, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl, amido, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
In another embodiment, R 9Be amino-heteroaryl (as-NH-heteroaryl, as aminothiazole base (thioazolyl)).Described thiazolyl substituting group can replace with the substituting group as benzyl ring.Following scheme 3 shows the representative substituting group of described thiazole (thioazole) ring.For example, in one embodiment, described thiazole can be used replacements such as phenyl group, xenyl group, adamantyl group.The substituting group of this thiazole also can further be substituted, as replacing with an electron-donating group or an electron-withdrawing group.The example of electron-withdrawing substituent comprises aromatic yl group (as phenyl), halogen (as chlorine, bromine or fluorine), alkoxy base (as methoxyl group, oxyethyl group), amine (as secondary amine, as diethylamine, dimethylamine, unsubstituted amine etc.), nitryl group etc.In other embodiment, (O-), alkyl or other key that allows the tetracycline compound of described replacement to fulfil its expectation function are connected in tetracycline compound to described thiazole basic ring by an ether.
For example, in one embodiment, R 9Be that replace or unsubstituted heteroaryl-amino, as, thiazolyl amino.The substituent example of described heteroaryl comprises; but be not limited to alkyl; alkenyl; halogen; hydroxyl; alkoxyl group; alkyl carbonyl oxy; alkoxy carbonyl; aryl-carbonyl oxygen; alkoxycarbonyl amino; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkyl amino-carbonyl; aralkyl; aminocarboxyl; the alkenyl amino carbonyl; alkyl-carbonyl; aryl carbonyl; aminoalkyl group; aromatic alkyl carbonyl; alkenyl carbonyl; alkoxy carbonyl; silyl; aminocarboxyl; the alkylthio carbonyl; phosphoric acid ester; aralkyl; phosphonate group; phosphinato; cyano group; amino; acyl amino; amido; imino-; sulfydryl; alkylthio; sulfuric ester; arylthio; carbothioic acid ester; alkyl sulphinyl; sulfonic group; sulfamyl; sulfonamido; nitro; cyano group; azido-; heterocyclic radical; alkaryl; aryl and heteroaryl.
In certain embodiments, the substituting group of described thiazolyl comprise alkyl (as methyl, ethyl, propyl group, butyl etc.), halogen (as fluorine, bromine, chlorine, iodine etc.), alkoxyl group (as methoxyl group, propoxy-, oxyethyl group etc.), aryl (as replace or unsubstituted phenyl or heteroaryl).
In one embodiment, described aryl thiazole base substituting group replaces with one or more substituting groups.Substituent example comprises; but be not limited to alkyl (as methyl, ethyl, propyl group, butyl etc.), alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, amido, trifluoromethyl, halogen, nitro, azo-group, alkyl sulphonyl, alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl etc.), aryloxycarbonyl and aryl sulfonyl.
Term " tetracycline compound that 7-replaces " is included in 7 tetracycline compounds that replacement is arranged.Can be easily comprise tsiklomitsin, Sancycline, Vibravenos, terramycin, Demethylchlortetracycline or metacycline at the example of the tetracycline compound of 7 replacements.In an advantageous embodiment, R 7Be NR 7cC (=W ') WR 7a, R wherein 7cCan be hydrogen, W ' can be oxygen or sulphur.R 7aCan be hydrophobic.R 7aAlso can be alkyl, alkenyl (as vinyl, propenyl, butenyl etc.), alkynyl, aryl (as phenyl, heteroaryl etc.), aralkyl, heteroaryl or many rings (for example many rings are as the steroid base, as cholesteryl).R 7aAlso can comprise at least one phenyl group, as naphthyl or fluorenes.In a preferred embodiment, W is oxygen or NR 7b, R wherein 7bBe hydrogen.
In one embodiment, R 7aFor replace or unsubstituted alkyl (as methyl, ethyl, the tertiary butyl, normal-butyl, isobutyl-or n-pentyl).Possible substituent example includes but not limited to alkyl; alkenyl; halogen; hydroxyl; alkoxyl group; alkyl carbonyl oxy; alkoxy carbonyl; aryl-carbonyl oxygen; alkoxycarbonyl amino; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkyl amino-carbonyl; aralkyl; aminocarboxyl; the alkenyl amino carbonyl; alkyl-carbonyl; aryl carbonyl; aminoalkyl group; aromatic alkyl carbonyl; alkenyl carbonyl; alkoxy carbonyl; silyl; aminocarboxyl; the alkylthio carbonyl; phosphoric acid ester; aralkyl; phosphonate group; phosphinato; cyano group; amino; acyl amino; amido; imino-; sulfydryl; alkylthio; sulfuric ester; arylthio; carbothioic acid ester; alkyl sulphinyl; sulfonic group; sulfamyl; sulfonamido; nitro; cyano group; azido-; heterocyclic radical; alkaryl; aryl and heteroaryl.In certain embodiments, described substituting group is alkoxy carbonyl, amino, aryl carbonyl, halogen, hydroxyl, alkylamino, alkoxyl group or aryl.In certain embodiments, described substituting group is halogen (as bromine, chlorine, iodine, a fluorine).In one embodiment, R 7aComprise at least one aromatic yl group, as heteroaryl, phenyl, naphthyl, fluorenes etc.
In one embodiment, R 7aBe aryl, as that replace or unsubstituted phenyl.Substituent example comprises; but be not limited to; alkyl (as; unsubstituted alkyl such as methyl, ethyl, propyl group, butyl, or the alkyl that replaces such as chloromethyl, dichloromethyl, perchloro-methyl, methyl fluoride, difluoromethyl, perfluoro-methyl etc.), alkenyl, alkynyl, aryl, alkoxyl group (as methoxyl group, oxyethyl group, propoxy-etc.), aryloxy, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl, amido, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
In another embodiment, R 7Be amino-heteroaryl (as-NH-heteroaryl, as the amino-thiazolyl-base).This thiazolyl substituting group can replace with the substituting group as benzyl ring.Following scheme 3 shows some representative substituting groups of described thiazole ring.For example, in one embodiment, described thiazole can be used replacements such as phenyl group, xenyl group, adamantyl group.The substituting group of this thiazole also can further be substituted, as replacing with an electron-donating group or an electron-withdrawing group.The example of electron-withdrawing substituent comprises aromatic yl group (as phenyl), halogen (as chlorine, bromine or fluorine), alkoxy base (as methoxyl group, oxyethyl group), amine (as secondary amine, as diethylamine, dimethylamine, unsubstituted amine etc.), nitryl group etc.In other embodiment, (O-), alkyl or other key that allows the tetracycline compound of described replacement to fulfil its expectation function are connected in tetracycline compound to described thiazole basic ring by ether.
For example, in one embodiment, R 7Be that replace or unsubstituted heteroaryl-amino, as, thiazolyl amino.The substituent example of described heteroaryl comprises; but be not limited to alkyl; alkenyl; halogen; hydroxyl; alkoxyl group; alkyl carbonyl oxy; alkoxy carbonyl; aryl-carbonyl oxygen; alkoxycarbonyl amino; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkyl amino-carbonyl; aralkyl; aminocarboxyl; the alkenyl amino carbonyl; alkyl-carbonyl; aryl carbonyl; aminoalkyl group; aromatic alkyl carbonyl; alkenyl carbonyl; alkoxy carbonyl; silyl; aminocarboxyl; the alkylthio carbonyl; phosphoric acid ester; aralkyl; phosphonate group; phosphinato; cyano group; amino; acyl amino; amido; imino-; sulfydryl; alkylthio; sulfuric ester; arylthio; carbothioic acid ester; alkyl sulphinyl; sulfonic group; sulfamyl; sulfonamido; nitro; cyano group; azido-; heterocyclic radical; alkaryl; aryl and heteroaryl.
In certain embodiments, the substituting group of described thiazolyl comprise alkyl (as methyl, ethyl, propyl group, butyl etc.), halogen (as fluorine, bromine, chlorine, iodine etc.), alkoxyl group (as methoxyl group, propoxy-, oxyethyl group etc.), aryl (as replace or unsubstituted phenyl or heteroaryl).
In one embodiment, described aryl thiazole base substituting group replaces with one or more substituting groups.Substituent example comprises; but be not limited to alkyl (as methyl, ethyl, propyl group, butyl etc.), alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, amido, trifluoromethyl, halogen, nitro, azo-group, alkyl sulphonyl, alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl etc.), aryloxycarbonyl and aryl sulfonyl.
In another one embodiment of the present invention, the R of the tetracycline compound of replacement 2 ', R 3, R 10, R 11And R 12Each is a hydrogen atom.In addition, in another embodiment, R 4And R 4 'Each is an alkyl, as low alkyl group, and is preferably methyl.In another embodiment, X is CR 6R 6 'R 6And R 6 'Be selected from hydrogen, methyl and oh group.
In another embodiment, the present invention also relates to wherein R 9And R 7Neither is the compound of hydrogen.These compounds can be described as 7-and the dibasic compound of 9-.The present invention relates to the compound of 7-of having disclosed herein and the substituent any associating of 9-.
Outside the compound of listing down, the example of The compounds of this invention comprises those disclosed compounds in table 2.The present invention also relates to the pharmacy acceptable salt of any one these compound and the mixture of enantiomorph and described compound.The example of The compounds of this invention includes but not limited to:
Vibravenos 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-base (Naphthyn-1-yl)) Vibravenos) urea;
9-(3-methyl isophthalic acid-butyl) Vibravenos urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Vibravenos urea;
The amino Vibravenos of FMOC 9-;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos urea;
9-(4 '-fluorophenyl) Vibravenos carbamate;
9-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 9-BOC;
The amino Vibravenos of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(ethyl thiazole base);
(4-fluorophenyl thiazolyl) amino Vibravenos;
The amino Vibravenos of 9-(4 '-p-methoxy-phenyl thiazolyl);
The amino Vibravenos of 9-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Minocycline HCl carbamate;
The amino Sancycline of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(adamantyl thiazolyl);
9-(naphthalene-1-base urea) Vibravenos 5-propionic ester;
Vibravenos 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Vibravenos) thiocarbamide;
9-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
9-phenyl Vibravenos thiocarbamide;
9-tertiary butyl Vibravenos thiocarbamide;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
9-(4 '-fluorophenyl) Vibravenos thiocarbamate;
9-(4-p-methoxy-phenyl) Vibravenos thiocarbamate;
9-neo-pentyl Minocycline HCl thiocarbamate;
9-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
Minocycline HCl 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl urea;
9-(3-methyl isophthalic acid-butyl) Minocycline HCl urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Minocycline HCl urea;
FMOC 9-amino minocycline ring element;
9-(4 '-chloro-2 '-trifluoromethyl) Minocycline HCl urea;
9-(4 '-fluorophenyl) Minocycline HCl carbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl carbamate;
9-BOC amino minocycline ring element;
9-(phenyl thiazole base) amino minocycline ring element;
9-(ethyl thiazole base) amino minocycline ring element;
(4 '-fluorophenyl thiazolyl) amino minocycline ring element;
9-(4 '-p-methoxy-phenyl thiazolyl) amino minocycline ring element;
9-9-(3 '-nitrophenyl thiazolyl) amino minocycline ring element;
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Vibravenos carbamate;
9-(phenyl thiazole base) amino minocycline ring element;
9-(adamantyl thiazolyl) amino minocycline ring element;
Minocycline HCl 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl thiocarbamide;
9-(3 '-methyl isophthalic acid-butyl) Minocycline HCl thiocarbamide;
9-phenyl Minocycline HCl thiocarbamide;
9-tertiary butyl Minocycline HCl thiocarbamide;
9-(4 '-fluorophenyl) Minocycline HCl thiocarbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl thiocarbamate;
9-neo-pentyl Vibravenos thiocarbamate;
9-(2 '-bromotrifluoromethane) Vibravenos carbamate;
9-(n-pentyl) Minocycline HCl carbamate;
The amino Vibravenos of 9-(4 '-benzoyl benzoyl);
The amino Sancycline of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(3 '-ethoxy carbonyl thiazolyl);
7-(4 '-aminomethyl phenyl) Sancycline carbamate;
9-(4 '-Trifluoromethoxyphen-l) Minocycline HCl urea;
9-(3 ', 5 '-two perfluorophenyls) Minocycline HCl thiocarbamide;
9-third-2 '-thiazolinyl Minocycline HCl carbamate;
9-(4 '-chlorine, 2 '-nitrophenyl) Minocycline HCl urea;
9-ethyl Minocycline HCl carbamate;
9-normal-butyl Minocycline HCl carbamate;
The positive fourth of 9--3-thiazolinyl Minocycline HCl carbamate;
Vibravenos 7-carboxylamine 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos urea;
7-(3-methyl isophthalic acid-butyl) Vibravenos urea;
7-phenyl Vibravenos urea;
7-tertiary butyl Vibravenos urea;
The amino Vibravenos of 7-Fmoc;
7-(4 '-chloro-2-trifluoromethyl) Vibravenos urea;
7-(4 '-fluorophenyl) Vibravenos carbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 7-BOC;
The amino Vibravenos of 7-(3 '-phenyl thiazole base);
The amino Vibravenos of 7-(3 '-ethyl thiazole base);
7-(4 "-the fluorophenyl thiazolyl) amino Vibravenos;
7-(4 "-the p-methoxy-phenyl thiazolyl) amino Vibravenos;
7-(phenyl thiazole base amino)-Sancycline;
The amino Vibravenos of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 7-(4 '-methyl, 5 '-phenyl thiazole base);
The amino Vibravenos of 7-(adamantyl thiazolyl);
Vibravenos 7-thiocarbamate 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos thiocarbamide;
7-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
7-phenyl amino Vibravenos thiocarbamide;
The amino Vibravenos thiocarbamide of the 7-tertiary butyl;
7-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
7-(4 '-fluorophenyl) Vibravenos thiocarbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos thiocarbamate;
7-(naphthalene-1-yl) Vibravenos urea 5-propionic ester;
9-isobutyl-Minocycline HCl carbamate;
7-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester,
And pharmacy acceptable salt.
Other compound of the present invention comprises the compound with following structure:
The R that the present invention includes preferably at formula (I) tetracycline compound 7And/or R 9Reactive intermediate is used in the position, as thiocarbamide, thiocarboxamide and diazonium salt, and the method for the tetracycline compound that synthetic 7-and/or 9-replace.In one embodiment, the present invention relates to by under suitable condition, making reactive intermediate contact the method for the tetracycline compound of synthetic 9-and/or 7-replacement with suitable reagent, so that form the tetracycline compound of a kind of 7-and/or 9-replacement.Suitable reagent and condition are described among scheme 1-3 and the embodiment 1.
Term " reactive intermediate " is included in the kind that produces during formula (I) tetracycline compound of synthetic 7-and/or 9-replacement.These intermediates can be stable or unsettled and separable or inseparable under reaction conditions., those skilled in the art will appreciate that these reactive intermediates can be used for producing the tetracycline compound of other 7-and/or 9-replacement.Term " reactive intermediate " comprises that all synthetic maybe can be used in the method synthetic intermediate of this discussion.The example of reactive intermediate of the present invention comprises 7-and/or 9-diazonium salt, 7-and/or 9-thiocarboxyl group amates (thiocarboxyamates), 7-and/or 9-anilino compound, 7-and/or 9-amino tetracycline compound, 7-and/or 9-nitrocycline compound, 7-and/or 9-urea derivatives, 7-and/or 9-carbamate derivatives etc.
Term " suitable condition " comprises condition known in the art and condition described herein, the tetracycline compound or another the required tetracycline compound that replace with the 7-that described reactive intermediate is converted into formula (I) and/or 9-.
Term " suitable reagent " comprises reagent known in the art and reagent described herein, with tetracycline compound or another the required tetracycline compound that described reactive intermediate is converted into formula (I).
In another embodiment, present invention resides in the method for the tetracycline compound that the synthetic 7-that summarizes in the following scheme and/or 9-replace.Although only show one or two tetracycline compound in reaction described in each scheme, it should be appreciated by those skilled in the art that with other tetracycline compound and also can similarly react.
In one embodiment, thus the present invention relates to by a kind of unsubstituted tetracycline compound is contacted with nitrating agent so that form a kind of 7-and/or the method for the tetracycline compound that the synthetic 7-of tetracycline compound that the 9-nitro replaces and/or 9-replace.Make the tetracycline compound hydrogenation of this 7-and/or the replacement of 9-nitro with hydrogenant agent so that form a kind of 7-and/or the amino tetracycline compound that replaces of 9-then.The amino tetracycline compound that replaces of this 7-and/or 9-is contacted with a kind of amino-reactive compound, form the tetracycline compound that a kind of 7-and/or 9-replace thus.
Term " nitrating agent " is included under the suitable condition can introduce nitryl group (NO 2) compound and chemical in the tetracycline compound.For example, favourable nitrating agent comprises: NaNO 2Be also included within other nitrifying method as known in the art and (for example, see March, Advanced Organic Chemistry, John Wiley ﹠amp; Sons:New York, 1992, the 522-525 page or leaf, and be incorporated herein by reference).Easily, when described nitrating agent be NaNO 2The time, this is reflected under the acidic conditions and carries out.
Term " hydrogenant agent " is included under the suitable condition can be converted into nitryl group amino group (NH 2) compound and chemical.The example of preferred hydrogenant agent comprises the H with transition-metal catalyst 2Gas, the preferred platinum of transition-metal catalyst.Other method that transforms nitryl group and be amino group is known in the artly (for example, to see March, Advanced OrganicChemistry John Wiley ﹠amp; Sons:New York, 1992, the 1216-1217 page or leaf, and be incorporated herein by reference).
Term " amino-reactive compound " comprises and can form a kind of required 7-and/or the tetracycline compound of 9-replacement or the compound and the molecule of its precursor with 7-and/or 9-amino tetracycline derivatives reaction.The favourable amino-reactive examples for compounds that forms urea that 9-replaces and carbamate tetracycline compound comprise replacement with unsubstituted isocyanic ester and chloro-formic ester.Following scheme 1 has been described the synthetic of Vibravenos compound that 9-replaces, and this method can be used for the tetracycline compound that other tetracycline compound and 7-replace.Described method comprises with acid (as H 2SO 4) and nitrating agent (as SODIUMNITRATE or saltpetre) handle unsubstituted tetracycline compound (1-1) so that form the tsiklomitsin intermediate (1-2) that reactive nitro replaces.The tsiklomitsin intermediate that this reactivity nitro replaces can with hydrogenant agent known in the art (as with metal catalyst, hydrogen together such as platinum oxide) be reduced to corresponding amine (1-3) so that produce the tetracycline compound (1-3) of amino replacement.The tetracycline compound (1-3) that then should amino replaces can form the tetracycline compound (1-5) that the blended urea replaces with isocyanic ester (1-4) reaction that replaces in weak base.The tetracycline compound (1-3) that this amino replaces also can with replace or unsubstituted chloro-formic ester (1-6) reaction form the carbamate tetracycline compound (1-7) that replaces.In addition, the tetracycline compound (1-3) that this amino replaces can with the compound of other kind, reaction forms other required derivative as isothiocyanic acid ester (1-8), as thiocarbamide (1-9).
Scheme 1
The initial nitrification of described tetracycline compound can produce the isomer mixture of 7-and 9-replacement.Those skilled in the art can understand after above-mentioned any reaction can pass through conventional method separating isomerism body.The technology of separating isomerism body is well-known in the art.For example, the described amino tetracycline compound (as 1-3) that replaces can separate with other positional isomers as the preparation HPLC with a binary gradient system on the C18-reverse phase silica gel by technology known in the art.Also can prepare described amino tetracycline compound according to No. 3,483,251, the U.S patent alkylating by the reductibility of 7-(N, N "-dicarbapentaborane benzyloxy diazanyl) tsiklomitsin.In addition, the tetracycline compound of other 7-and/or 9-replacement can synthesize by making the reaction of described amino intermediate and amino reaction substrate.
Reactive 7-and/or the amino tetracycline compound that replaces of 9-have been comprised as reactive intermediate.The tetracycline compound that this amino replaces can with compound such as the isocyanate derivates or the lsothiocyanates derivatives reaction of other chemical classes, produce 7-and/or 9-position urea and thiocarbamide (thiocarbonyl carboxylic acid amides) shown in scheme 1.7-and/or 9-position urea and thiocarbamide tetracycline compound are reactive intermediates and can be used for many kinds of 7-and/or tetracycline compound that 9-replaces synthetic.For example, described 7-and/or 9-position thiocarbamide can be by being used to form amino-heterocyclic group in the reaction shown in the following scheme 2.
Scheme 2
Figure A0181013200421
For example, the amino tetracycline compound (2-1) that replaces of 9-can produce the tetracycline compound (2-2) that the 9-Fmoc thiocarbamide replaces with the Fmoc-NCS reaction.The available methods known in the art of tetracycline compound (2-2) that this Fmoc substituting thioureido replaces remove to protect the tetracycline compound (2-3) that forms the replacement of 9-thiocarbamide.The tetracycline compound (2-3) that this 9-thiocarbamide replaces is a kind of reactive intermediate, it can with α-Lu Daitong (2-4, as replace or unsubstituted α-Lu Daitong etc.) reaction, produce the amino tetracycline compound (2-5) that replaces of 9-thiazolyl.This method also can be used for forming tsiklomitsin reactive intermediate and the 7-position thiazolyl amino tetracycline compound that 7-position thiocarbamide replaces.
Thiocarbamide tsiklomitsin reactive intermediate also can be used as reactive intermediate in following compound synthetic, described compound has for example volution and condensed ring penta pyrazoles (cyclopentapyrozole) and pyrimidine derivatives (Albar etc., J.Chem.Res., Synop., (2), 40-41 (1997)), pyridazine derovatives (sharaf El-Din, Alexandria J.Pharm.Sci., 11 (1) 9-12 (1997)), benzothiazole acrylic acid derivative (Kassem etc., Pak.J.Sci.Ind.Res.38 (11-12) 424-427 (1995)), thiazoline, arylazo thiazole (aryazothioazole) and pyrazole derivatives (Abdelhamid, A.Phosphorous, Sulfur, Silicon Related Elem.119 (181-191) (1996)), pyrimidine derivatives (Fikry, J.Indian Chem.Soc., 73 (12), 698-699 (1996)), aminothiazole-carbonitrile derivatives (Shiono, JP95-331456), benzimidizole derivatives (Omar etc., Egypt.J.Pharm.Sci.37 (1-6), 609-620 (1996)), benzyl tetrahydrothiazole derivates (Morita etc., JP 95-200268), clonidine derivative (Pierce etc., WO95/21818), pyrimidine derivatives (Nassar etc., Egypt.J.Chem.40 (3), 239-247 (1997)), bicyclic derivatives (Zhu etc., Hanneng Cailiao 5 (4), 165-170 (1997)), combinatorial libraries (combinatoria1 libraries) (Nefzi etc., WO98/19693), three Oxazinobenzazole derivative (Tomchin etc., Khim.-Farm.Zh., 31 (3) 19-27 (1997); Tomchin etc., Khim.-Farm.Zh., 32 (3) 7-10 (1998)), aryl thio derivative (Chikalia etc., Proc.Nat.Acad Sci.India 68 (A), I, 1998) and alpha-amino acid derivatives (Beyer etc., Tetrahedron, 52 (17) 6233-6240 (1996)).
Scheme 3
Described according to scheme 3, can be dissolved in the strong acid by the tetracycline compound that 7-and/or 9-are replaced and add suitable carboxylic acid and form 3 of tetracycline compound (3-1 and 3-3) that 7-and/or 9-replace, 5-ester.The example of strong acid comprises anhydrous hydrogen fluoride, methylsulfonic acid and trifluoromethanesulfonic acid.
The present invention also relates to a kind of under suitable condition by making a kind of reactive intermediate contact the method for the tetracycline compound of the 7-of synthesis type (I) or 9-replacement with suitable reagent, so that form a kind of tetracycline compound of replacement.Formula (I) compound and pharmacy acceptable salt thereof have following formula:
Figure A0181013200442
Wherein:
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl-amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, NR 9cC (=Z ') ZR 9a, or heteroaryl-amino
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist, or the prodrug part;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist, or the prodrug part;
Condition is to work as R 7R during for dialkyl amido or hydrogen 9Be not hydrogen.
In one embodiment, this reactive intermediate is 7-and/or 9-diazonium salt, 7-and/or 9-nitro-compound, 7-and/or 9-thiocarbamide or 7-and/or 9-thiocarboxamide.
The present invention also relates to the reactive intermediate and the pharmacy acceptable salt thereof of following formula:
Figure A0181013200461
Wherein:
X is CHC (R 13Y ' Y), CHR 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, thiocarbamide, diazonium salt, thiocarboxamide or nitro;
R 7Be hydrogen, thiocarbamide, dialkyl amido, diazonium salt, thiocarboxamide or nitro;
Condition is to work as R 7R during for hydrogen or dialkyl amido 9Be not hydrogen.
In another embodiment, work as R 9During for thiocarbamide, diazonium salt, thiocarboxamide or nitro, R 7Be hydrogen or dialkyl amido.In another embodiment, work as R 7R during for thiocarbamide, diazonium salt, thiocarboxamide or nitro 9Be hydrogen.
Unless otherwise indicated, chemical group of the present invention can be replacement or unsubstituted.In addition, unless otherwise indicated, described chemical substituting group can be substituted successively or not replace.In addition, on a chemical group or substituting group, can there be a plurality of substituting groups.Substituent example comprises alkyl; alkenyl; alkynyl; halogen; hydroxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxyl; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; aminocarboxyl; alkyl amino-carbonyl; dialkyl amino carbonyl; the alkylthio carbonyl; alkoxyl group; formyl radical; trimethyl silyl; phosphonic acid ester; phosphonate group; phosphinato; cyano group; amino (comprises alkylamino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; formamyl and urea groups); amido; imino-; sulfydryl; alkylthio; arylthio; carbothioic acid ester; sulfuric ester; alkyl sulphinyl; sulfonic group; sulfamyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido-; heterocyclic radical; alkaryl; aryl or heteroaryl; cholesterol; aryl sulfonyl; azo-group; thiazolyl; adamantyl and phosphono.
Term " alkyl " comprises saturated fat group, comprises straight chained alkyl group, branched alkyl group, cycloalkyl (alicyclic) group, the group of naphthene base of alkyl replacement and the alkyl group of cycloalkyl substituted.The term alkyl comprises the alkyl group that can further comprise the oxygen, nitrogen, sulphur or the inferior phosphorus atom that replace the carbon atom on one or more hydrocarbon main chains in addition, as oxygen, nitrogen, sulphur or inferior phosphorus atom.In one embodiment, the straight or branched alkyl is containing carbon atom below 10 or 10 (as C on its main chain 1-C 10Straight chain, C 3-C 10Side chain), and in another embodiment, have 4 or less than 4 carbon atoms.Equally, in certain embodiments, cycloalkyl has 4-7 carbon atom on its ring structure, and can have 5 or 6 carbon atoms on this ring structure.
In addition, the term alkyl comprise " unsubstituted alkyl " and " alkyl of replacement " both, the latter relates to the substituent alkyl group with hydrogen atom on the one or more carbon atoms that replace the hydrocarbon main chain.For example, this type of substituting group can comprise halogen; hydroxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkoxy carbonyl; aminocarboxyl; the alkylthio carbonyl; alkoxyl group; phosphoric acid ester; phosphonate group; phosphinato; cyano group; amino (comprises alkylamino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; formamyl and urea groups); amidino groups; imino-; sulfydryl; alkylthio; arylthio; carbothioic acid ester; sulfuric ester; sulfonic group; sulfamyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido-; heterocyclic radical; alkaryl; aryl or heteroaryl.Cycloalkyl can further be substituted, as replacing with above-mentioned substituting group." alkaryl " group is the alkyl (as phenyl methyl (benzyl)) that is replaced by aryl.
Term " aryl " comprises aromatic yl group, comprise and to comprise zero to four heteroatomic 5-and 6-unit monocyclic aromatic group, for example benzene, pyrroles, furans, thiophene, imidazoles, benzoxazole, benzothiazole, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc.Ring condensed aromatic groups such as naphthyl, quinolyl, indyl etc. more than aromatic yl group also comprises.Those contain heteroatomic aromatic yl group and also can be described as " aryl-heterocyclic ", " heteroaryl " or " assorted aromatic base " in ring structure.Described aromatic ring can replace with aforesaid substituting group on one or more ring positions, and described substituting group has for example halogen; hydroxyl; alkoxyl group; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkoxy carbonyl; aminocarboxyl; the alkylthio carbonyl; phosphoric acid ester; phosphonate group; phosphinato; cyano group; amino (comprises alkylamino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; formamyl and urea groups); amidino groups; imino-; sulfydryl; alkylthio; arylthio; carbothioic acid ester; sulfuric ester; sulfonic group; sulfamyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido-; heterocyclic radical; alkaryl; aryl or heteroaryl.Aromatic yl group also can with the alicyclic ring of non-fragrance heterocyclic ring condenses or bridge joint so that form many rings (as 1,2,3,4-tetralins).
Term " alkenyl " and " alkynyl " comprise unsubstituted fat group, and it is similar to above-mentioned alkyl on length and possible substituting group, but they contain two keys or triple bond at least respectively.
The quantity of carbon atom except as otherwise noted, otherwise " low alkyl group " means alkyl group as defined above when this uses, but contains 1 to 5 carbon atom on its backbone structure.Equally, " low-grade alkenyl " and " low-grade alkynyl " has similar chain length.
Term " alkoxyalkyl ", " polyamino alkyl " and " thio alkoxy alkyl " comprise aforesaid alkyl group, this alkyl group further contains oxygen, nitrogen or the sulphur atom that replaces the one or more carbon on this hydrocarbon main chain, as oxygen, nitrogen or sulphur atom.
Term " many cyclic groups " " many rings " or " many cyclic groups " refer to two or more cyclic rings (as cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), for two adjacent rings, two or more carbon wherein have, and for example described ring is " condensed ring ".The ring that connects by non-adjacent atom is called " bridge " ring.Each ring of polycyclic can replace with aforesaid substituting group, and described substituting group for example has halogen; hydroxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl group carbonyl oxygen base; aryloxy carbonyl oxygen base; carboxylicesters; alkyl-carbonyl; alkoxy carbonyl; aminocarboxyl; the alkylthio carbonyl; alkoxyl group; phosphoric acid ester; phosphonate group; phosphinato; cyano group; amino (comprises alkylamino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; formamyl and urea groups); amidino groups; imino-; sulfydryl; alkylthio; arylthio; carbothioic acid ester; sulfuric ester; sulfonic group; sulfamyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido-; heterocyclic radical; alkyl; alkaryl; or fragrance or assorted aromatic group.The example of " many rings " part comprises steroide, as cholesterol.
When this uses, term " heteroatoms " means the atom of the arbitrary element except carbon or hydrogen.Preferred heteroatoms is nitrogen, oxygen, sulphur and phosphorus.
Suitable alkanoyl group comprises and contains 1 group to about 4 or 5 carbonyls.Suitable aroyl group comprises having the substituent group of one or more carbonyl groups as aromatic yl group such as phenyl or other isocyclic aryl.Suitable alkane aroyl group contains the substituent one or more alkyl-carbonyl groups as aromatic yl group, as phenyl acetyl etc.Suitable carbon ring aromatic yl group contains 6 or 6 above carbon such as phenyl, naphthyl etc.Suitable aryl-acyl group is typically the carbon ring aromatic yl group that replaces with 1 or 2 carbonyl group for to use one or more carbonyl groups.
Prodrug for the compound that is converted into activity form in vivo (as, see R.B.Silverman, 1992, " The Organic Chemistry of Drug Design and Drug Action (medicinal design and pharmaceutically-active organic chemistry) ", Academic Press, Chp.8).For a kind of particular compound, prodrug can be used for changing bio distribution (as, the compound that allows to enter the reaction site of proteolytic enzyme usually enters) or pharmacokinetics.For example, an oh group can produce a kind of ester with a hydroxy-acid group esterification.When giving a patient with described ester, this ester is through enzymolysis or non-enzymolysis, reduction or hydrolysis and cracking exposes described oh group.
Term " prodrug part " comprises in vivo the group that can metabolism produces active compound.For example, this term comprises the part of some functional group of the tetracycline compound that can modify described replacement, for example, but is not limited to oh group and amino group.In one embodiment, described prodrug part is oh group, amino, amido or other group by esterase or by other machine-processed metabolism in vivo, and they allow the tetracycline compound of described replacement to fulfil the function of its expection.The purposes of the example of prodrug and they be well known in the art (as, see (1997) such as Berge " Pharmaceutical Salts (pharmaceutical salts) ", J.Pharm.Sci.66:1-19).During the last separation and purifying of described compound, can prepare the some drugs precursor in the original place, or the compound by making purifying respectively is with its free acid form or hydroxyl and a kind of suitable some prodrugs of esterifying reagent prepared in reaction.For example, oh group can be converted into ester through handling with a kind of carboxylic acid (for example, square case 3).The example of prodrug part comprise replacement with unsubstituted, the low alkyl group ester moiety (as propionic ester) of side chain or non-side chain, the low-grade alkenyl ester, two low alkyl groups-amino lower alkyl esters (as dimethylamino ethyl ester), amido lower alkyl esters (as the acetoxyl group methyl esters), acyloxy lower alkyl esters (as the new pentane acyloxy methyl esters), aryl ester (phenylester), aryl lower alkyl ester (as benzyl ester), replace (as using methyl, halogeno-group or methoxyl group substituting group replace) aryl and aryl lower alkyl ester, acid amides, the low alkyl group acid amides, two low alkyl group acid amides, and oxyamide.Preferred prodrug partly is propionic ester and acyl ester for oh group.Amino or amido group can be modified formation Schiff alkali by methods known in the art in vivo can or cannot metabolic prodrug with other.
The structure that should be noted that compounds more of the present invention comprises unsymmetrical carbon.Therefore, should be appreciated that, unless otherwise indicated, comprise within the scope of the invention, can obtain this type of isomer with pure form fully by typical isolation technique with by stereochemical control is synthetic otherwise plant the isomer (as all enantiomorphs and diastereomer) that asymmetry produces thus.
Thereby the present invention also discloses a kind of method of reactive disorder state of the tetracycline compound that gives patient treatment patient by the tetracycline compound with replacement of the present invention.Preferably give the substituted tetracycline compound of significant quantity.In one embodiment, the tetracycline compound of described replacement has formula (I).The present invention includes the method for the reactive disorder state of any one treatment tetracycline compound in the compound that uses above-claimed cpd or in following table 2, list.
Term " patient " comprises any animal or plant that maybe can obtain some benefit from give substituted tetracycline compound of the present invention for the treatment of.This term also comprises animal (as bird, reptile, fish), Mammals (as cow, pig, sheep, horse, ox, dog, cat, squirrel, bear, monkey, chimpanzee, gorilla, goat, ferret, also preferred human).The reactive disorder state that described patient is just suffering from tetracycline compound usually maybe may be in the danger of the reactive disorder state of suffering from tetracycline compound.In one embodiment, it is impaired that described patient can be immunizing power, as suffer from AIDS, stand chemotherapy or recover from chemotherapy or suffer from immunological disease.
Term " the reactive disorder state of tetracycline compound " comprises can be by giving the morbid state of substituted tetracycline compounds for treating of the present invention, prevention or improvement.The reactive disorder state of tetracycline compound comprises that infectation of bacteria (comprising those infection to the opposing of other tetracycline compound), cancer, diabetes and other found that tetracycline compound to its effective morbid state (for example, see U.S. patent 5,789,395; 5,834,450; With 5,532, No. 227).The compounds of this invention also can be used for preventing or controls important Mammals and animal doctor's disease such as diarrhoea, urinary tract infection, skin and skin histology infection, ear, N﹠T infection, wound infection, mazoitis etc.In addition, also comprise the method (van der Bozert etc., Cancer res., 48:6686-6690 (1988)) for the treatment of tumour with tetracycline compound of the present invention.
Many kinds of Gram-positives and Gram-negative bacteria can cause infectation of bacteria.Compound of the present invention is as the microbiotic that suppresses microorganism, and described microorganism has resistivity to other tetracycline compound.The anti-microbial activity of tetracycline compound of the present invention can be used on the method for being discussed among the embodiment 2 and measures, or be described in Waitz by use, J.A., National Commissionfor Clinical Laboratory Standards (national clinical labororatory standard), Document M7-A2,10 volumes, No. 8,13-20 page or leaf, the 2nd edition, Villanova, the method among the PA (1990) is measured in external standard meat soup diluent.Intestinal bacteria
Also can use described tetracycline compound treatment to use the infection of tetracycline compound treatment traditionally, for example the infection of rickettsia, many Gram-positives and Gram-negative bacteria and described medicine comprise that to lymphogranuloma venereum conjunctivitis and psittacosis are effective.The tetracycline compound of described replacement can be used for treating pneumococcus (pneumococci), salmonella (Salmonella), intestinal bacteria (E.coli), streptococcus aureus (S.aureus), E.hirae or enterococcus faecalis (E.faecalis) to be infected.In one embodiment, the tetracycline compound of described replacement be used for the treatment of to other unsubstituted tetracycline antibiotics compound (as, such as the tetracycline compound of Vibravenos, Minocycline HCl, Sancycline or tsiklomitsin) drug-fast infectation of bacteria arranged.In another embodiment, compare with unsubstituted tetracycline compound, substituted tetracycline compound of the present invention has less cytotoxicity to the patient, and therefore described substituted tetracycline compound can give higher dosage and can not have fatal or undue toxicity to the patient.Substituted tetracycline compound of the present invention can give with pharmaceutically acceptable carrier.
The example that can be used for the The compounds of this invention of the inventive method expediently comprises the tetracycline compound of the replacement of formula (I) and the compound that is described in table 2.The example of The compounds of this invention comprises:
Vibravenos 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Vibravenos urea;
9-(3-methyl isophthalic acid-butyl) Vibravenos urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Vibravenos urea;
The amino Vibravenos of FMOC 9-;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos urea;
9-(4 '-fluorophenyl) Vibravenos carbamate;
9-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 9-BOC;
The amino Vibravenos of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(ethyl thiazole base);
(4-fluorophenyl thiazolyl) amino Vibravenos;
The amino Vibravenos of 9-(4 '-p-methoxy-phenyl thiazolyl);
The amino Vibravenos of 9-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Minocycline HCl carbamate;
The amino Sancycline of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(adamantyl thiazolyl);
9-(naphthalene-1-base urea) Vibravenos 5-propionic ester;
Vibravenos 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Vibravenos thiocarbamide;
9-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
9-phenyl Vibravenos thiocarbamide;
9-tertiary butyl Vibravenos thiocarbamide;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
9-(4 '-fluorophenyl) Vibravenos thiocarbamate;
9-(4-p-methoxy-phenyl) Vibravenos thiocarbamate;
9-neo-pentyl Minocycline HCl thiocarbamate;
9-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
Minocycline HCl 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl urea;
9-(3-methyl isophthalic acid-butyl) Minocycline HCl urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Minocycline HCl urea;
FMOC 9-amino minocycline ring element;
9-(4 '-chloro-2 '-trifluoromethyl) Minocycline HCl urea;
9-(4 '-fluorophenyl) Minocycline HCl carbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl carbamate;
9-BOC amino minocycline ring element;
9-(phenyl thiazole base) amino minocycline ring element;
9-(ethyl thiazole base) amino minocycline ring element;
(4 '-fluorophenyl thiazolyl) amino minocycline ring element;
9-(4 '-p-methoxy-phenyl thiazolyl) amino minocycline ring element;
9-9-(3 '-nitrophenyl thiazolyl) amino minocycline ring element;
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Vibravenos carbamate;
9-(phenyl thiazole base) amino minocycline ring element;
9-(adamantyl thiazolyl) amino minocycline ring element;
Minocycline HCl 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl thiocarbamide;
9-(3 '-methyl isophthalic acid-butyl) Minocycline HCl thiocarbamide;
9-phenyl Minocycline HCl thiocarbamide;
9-tertiary butyl Minocycline HCl thiocarbamide;
9-(4 '-fluorophenyl) Minocycline HCl thiocarbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl thiocarbamate;
9-neo-pentyl Vibravenos thiocarbamate;
9-(2 '-bromotrifluoromethane) Vibravenos carbamate;
9-(n-pentyl) Minocycline HCl carbamate;
The amino Vibravenos of 9-(4 '-benzoyl benzoyl);
The amino Sancycline of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(3 '-ethoxy carbonyl thiazolyl);
7-(4 '-aminomethyl phenyl) Sancycline carbamate;
9-(4 '-Trifluoromethoxyphen-l) Minocycline HCl urea;
9-(3 ', 5 '-two perfluorophenyls) Minocycline HCl thiocarbamide;
9-third-2 '-thiazolinyl Minocycline HCl carbamate;
9-(4 '-chlorine, 2 '-nitrophenyl) Minocycline HCl urea;
9-ethyl Minocycline HCl carbamate;
9-normal-butyl Minocycline HCl carbamate;
The positive fourth of 9--3-thiazolinyl Minocycline HCl carbamate;
Vibravenos 7-carboxylamine 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos urea;
7-(3-methyl isophthalic acid-butyl) Vibravenos urea;
7-phenyl Vibravenos urea;
7-tertiary butyl Vibravenos urea;
The amino Vibravenos of 7-Fmoc;
7-(4 '-chloro-2-trifluoromethyl) Vibravenos urea;
7-(4 '-fluorophenyl) Vibravenos carbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 7-BOC;
The amino Vibravenos of 7-(3 '-phenyl thiazole base);
The amino Vibravenos of 7-(3 '-ethyl thiazole base);
7-(4 "-the fluorophenyl thiazolyl) amino Vibravenos;
7-(4 "-the p-methoxy-phenyl thiazolyl) amino Vibravenos;
7-(phenyl thiazole base amino)-Sancycline;
The amino Vibravenos of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 7-(4 '-methyl, 5 '-phenyl thiazole base);
The amino Vibravenos of 7-(adamantyl thiazolyl);
Vibravenos 7-thiocarbamate 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos thiocarbamide;
7-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
7-phenyl amino Vibravenos thiocarbamide;
The amino Vibravenos thiocarbamide of the 7-tertiary butyl;
7-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
7-(4 '-fluorophenyl) Vibravenos thiocarbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos thiocarbamate;
7-(naphthalene-1-yl) Vibravenos urea 5-propionic ester;
7-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
9-isobutyl-Minocycline HCl carbamate, and pharmacy acceptable salt and prodrug.
Reactive disorder state necessary amount or the enough amount of the tetracycline compound of the replacement of term " significant quantity " for treating or preventing a kind of tetracycline compound.Described significant quantity can change according to the bodily form and body weight, the type of disease or the concrete factors such as substituted tetracycline compound as the patient.For example, the selection of substituted tetracycline compound can influence composition " significant quantity ".Those of ordinary skill in the art can study aforementioned factor and determine this replacement tetracycline compound significant quantity and do not have unsuitable experiment.
The present invention also relates to suppress the methods of treatment of infected by microbes and diseases related.Described method comprises the tetracycline compound of one or more replacements that give patient's significant quantity, and described patient can be plant or is preferably animal, as Mammals, as the people.
In methods of treatment of the present invention, the tetracycline compound of one or more replacements of the present invention can give the patient separately, or more typically, The compounds of this invention will as with a part of administration of conventional excipients blended medicinal compositions, described vehicle is the pharmaceutically acceptable organic or inorganic carrier substance that is applicable to parenterai administration, oral administration or other required mode administration, and adverse reaction and harmless to its recipient does not take place for they and active compound.
In one embodiment, the present invention relates to medicinal compositions, said composition contains the tetracycline compound of one or more foregoing replacements of the present invention.The present invention relates to contain the medicinal compositions of the tetracycline compound of described any replacement in this application.For example, the present invention relates to contain the medicinal compositions of the tetracycline compound of the replacement in formula (I) and the table 2.Other example that can be included in the substituted tetracycline compound of the present invention in the medicinal compositions of the present invention includes, but are not limited to:
Vibravenos 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Vibravenos urea;
9-(3-methyl isophthalic acid-butyl) Vibravenos urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Vibravenos urea;
The amino Vibravenos of FMOC 9-;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos urea;
9-(4 '-fluorophenyl) Vibravenos carbamate;
9-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 9-BOC;
The amino Vibravenos of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(ethyl thiazole base);
(4-fluorophenyl thiazolyl) amino Vibravenos;
The amino Vibravenos of 9-(4 '-p-methoxy-phenyl thiazolyl);
The amino Vibravenos of 9-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Minocycline HCl carbamate;
The amino Sancycline of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(adamantyl thiazolyl);
9-(naphthalene-1-base urea) Vibravenos 5-propionic ester;
Vibravenos 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Vibravenos thiocarbamide;
9-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
9-phenyl Vibravenos thiocarbamide;
9-tertiary butyl Vibravenos thiocarbamide;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
9-(4 '-fluorophenyl) Vibravenos thiocarbamate;
9-(4-p-methoxy-phenyl) Vibravenos thiocarbamate;
9-neo-pentyl Minocycline HCl thiocarbamate;
9-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
Minocycline HCl 9-carboxylamine 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl urea;
9-(3-methyl isophthalic acid-butyl) Minocycline HCl urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Minocycline HCl urea;
FMOC 9-amino minocycline ring element;
9-(4 '-chloro-2 '-trifluoromethyl) Minocycline HCl urea;
9-(4 '-fluorophenyl) Minocycline HCl carbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl carbamate;
9-BOC amino minocycline ring element;
9-(phenyl thiazole base) amino minocycline ring element;
9-(ethyl thiazole base) amino minocycline ring element;
(4 '-fluorophenyl thiazolyl) amino minocycline ring element;
9-(4 '-p-methoxy-phenyl thiazolyl) amino minocycline ring element;
9-9-(3 '-nitrophenyl thiazolyl) amino minocycline ring element;
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Vibravenos carbamate;
9-(phenyl thiazole base) amino minocycline ring element;
9-(adamantyl thiazolyl) amino minocycline ring element;
Minocycline HCl 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
(9-(naphthalene-1-yl) Minocycline HCl thiocarbamide;
9-(3 '-methyl isophthalic acid-butyl) Minocycline HCl thiocarbamide;
9-phenyl Minocycline HCl thiocarbamide;
9-tertiary butyl Minocycline HCl thiocarbamide;
9-(4 '-fluorophenyl) Minocycline HCl thiocarbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl thiocarbamate;
9-neo-pentyl Vibravenos thiocarbamate;
9-(2 '-bromotrifluoromethane) Vibravenos carbamate;
9-(n-pentyl) Minocycline HCl carbamate;
The amino Vibravenos of 9-(4 '-benzoyl benzoyl);
The amino Sancycline of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(3 '-ethoxy carbonyl thiazolyl);
7-(4 '-aminomethyl phenyl) Sancycline carbamate;
9-(4 '-Trifluoromethoxyphen-l) Minocycline HCl urea;
9-(3 ', 5 '-two perfluorophenyls) Minocycline HCl thiocarbamide;
9-third-2 '-thiazolinyl Minocycline HCl carbamate;
9-(4 '-chlorine, 2 '-nitrophenyl) Minocycline HCl urea;
9-ethyl Minocycline HCl carbamate;
9-normal-butyl Minocycline HCl carbamate;
The positive fourth of 9--3-thiazolinyl Minocycline HCl carbamate;
Vibravenos 7-carboxylamine 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos urea;
7-(3-methyl isophthalic acid-butyl) Vibravenos urea;
7-phenyl Vibravenos urea;
7-tertiary butyl Vibravenos urea;
The amino Vibravenos of 7-Fmoc;
7-(4 '-chloro-2-trifluoromethyl) Vibravenos urea;
7-(4 '-fluorophenyl) Vibravenos carbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 7-BOC;
The amino Vibravenos of 7-(3 '-phenyl thiazole base);
The amino Vibravenos of 7-(3 '-ethyl thiazole base);
7-(4 "-the fluorophenyl thiazolyl) amino Vibravenos;
7-(4 "-the p-methoxy-phenyl thiazolyl) amino Vibravenos;
7-(phenyl thiazole base amino)-Sancycline;
The amino Vibravenos of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 7-(4 '-methyl, 5 '-phenyl thiazole base);
The amino Vibravenos of 7-(adamantyl thiazolyl);
Vibravenos 7-thiocarbamate 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos thiocarbamide;
7-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
7-phenyl amino Vibravenos thiocarbamide;
The amino Vibravenos thiocarbamide of the 7-tertiary butyl;
7-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
7-(4 '-fluorophenyl) Vibravenos thiocarbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos thiocarbamate;
7-(naphthalene-1-yl) Vibravenos urea 5-propionic ester;
7-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
9-isobutyl-Minocycline HCl carbamate; And pharmaceutically can the connecing of above compound
Salt that is subjected to and prodrug.
Term " pharmaceutically acceptable carrier " comprises and can and allow the tetracycline compound of this replacement to fulfil the function of its expection with the tetracycline compound Combined Preparation of described replacement, as the material of the function of the reactive disorder state of treatment or prevention tsiklomitsin.Suitable pharmaceutically acceptable carrier includes but not limited to water, salts solution, alcohol, vegetables oil, polyoxyethylene glycol, gelatin, lactose, amylose starch, Magnesium Stearate, talcum powder, silicic acid, viscous paraffin, perfume oil, glycerine monofatty ester and two glyceryl ester, sherwood oil fatty acid ester, Walocel MT 20.000PV, polyvinylpyrrolidone etc.Medicinal preparations can be sterilized and if desired can for example lubricant, sanitas, stablizer, wetting agent, emulsifying agent, the salt that is used to influence osmotic pressure, damping fluid, tinting material, correctives and/or aromatoising substance etc. are mixed with the assistant agent that adverse reaction does not take place with active compound of the present invention.
The substituted tetracycline compound of the present invention that is essentially alkalescence can form many salt with various inorganic or organic acids.Can be used for preparing person's character and form the acid of avirulent acid salt for those for the acid of the pharmaceutically-acceptable acid addition of the tetracycline compound of the present invention of alkalescence, promptly contain pharmaceutically acceptable anionic salt, example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, Portugal (grape) sugar lime, saccharic acid salt (glucaronate), sugar lime, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (palmoate) [promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)].Though for giving patient such as Mammals, this type of salt must be pharmaceutically acceptable, but the in fact initial tetracycline compound that separates replacement of the present invention from reaction mixture is pharmaceutically unacceptable salt of conduct, be a kind of pharmaceutically-acceptable acid addition by handling the free alkali that simply latter is converted into again free basic cpd and subsequent transformation back with alkaline reagents then, this usually suits the requirements.By in water-containing solvent vehicle or in suitable organic solvent such as methyl alcohol or ethanol, inorganic or organic acid is handled the acid salt that this basic cpd is easy to prepare basic cpd of the present invention with a kind of selectivity of basic equivalent.Evaporate this solvent carefully, be easy to obtain required solid salt.
Be essentially tart substituted tetracycline compound of the present invention and can form many subsalt.Can be used as preparation those be essentially tart substituted tetracycline compound of the present invention pharmaceutically acceptable subsalt reagent chemical bases for those therewith compounds form the alkali of nontoxic subsalt.This type of nontoxic subsalt comprises, but be not limited to, those are from this type of pharmaceutically acceptable positively charged ion such as alkali metal cation (as potassium and sodium) and alkaline earth metal cation (as calcium and magnesium) deutero-salt, ammonium or water-soluble amine additive salt such as N-methylglucosamine-(meglumine) and low-level chain triacontanol ammonium and other pharmaceutically acceptable organic subsalt of pressing.The pharmaceutically acceptable base addition salt that is essentially tart tetracycline compound of the present invention can form by conventional method and pharmaceutically acceptable positively charged ion.Therefore, these salt can be easily by handling solution that tetracycline compound of the present invention and evaporation produced with the required pharmaceutically acceptable cationic aqueous solution to doing, best vapourisation under reduced pressure and being prepared.As selection, the low alkyl group alcoholic solution of substituted tetracycline compound of the present invention can mix with the alkoxide of required metal, evaporates this solution subsequently to doing.
The preparation of other tetracycline compound of the present invention of clearly not describing at aforesaid experimental section is finished in the combination of available above-mentioned reaction, and this will be conspicuous to those skilled in the art.
But substituted tetracycline compound of the present invention and pharmacy acceptable salt per os, parenteral or topical routes.Usually these compounds it would be desirable with the effective dose administration, and described effective dose depends on patient's body weight and the disease and the selected concrete route of administration of being treated.According to the species of patient of being treated and to the individual reaction and the selected types of drug preparations of described medicine and carry out the time of administration cycle and can change at interval.
Medicinal compositions of the present invention can be individually dosed or with other known compound Combined Preparation of the reactive disorder state of the mammiferous tsiklomitsin of treatment.Mammals preferably include pet (as, cat, dog, ferret etc.), domestic animal (ox, sheep, pig, horse, goat etc.), laboratory animal (rat, mouse, monkey etc.) and primates (chimpanzee, the mankind, gorilla).Term and a kind of known composition " associating " are planned to comprise and are given composition of the present invention and known composition simultaneously, at first give composition of the present invention, give known composition subsequently, and at first give known composition, give composition of the present invention subsequently.Any known therapeutic composition for the treatment of the reactive disorder state of tsiklomitsin in this area can be used for method of the present invention.
Substituted tetracycline compound of the present invention can give separately or unite with pharmaceutically acceptable carrier or thinner to give by aforesaid any approach, and can single dose or multiple dose administration.For example, novel treatment of the present invention can be easily with many different formulation administrations, and promptly they can be united with administrations such as tablet, capsule, lozenge, dragee, hard candy, powder, sprays, ointment, ointment, suppository, gelifying agent, gelinite, paste, lotion, ointment, aqeous suspension, injectable solution, elixir, syrups with various pharmaceutically acceptable inert supports.Examples of such carriers comprises solid diluent or weighting agent, sterile aqueous vehicle and various nontoxic organic solvents etc.In addition, oral medicinal compositions can be suitably sweet and/or fragrance.Usually, in the present invention's treatment-compounds effective is present in this type of formulation with about 5.0% concentration level to about 70% weight range.
For oral administration, the tablet that contains various vehicle such as Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and Padil can be used with granulation binders such as polyvinylpyrrolidone, sucrose, gelatinum and gum arabic together with various disintegrating agents such as starch (preferred corn, potato or tapioca (flour)), alginic acid and some composition silicate.In addition, for the purpose of film-making, make with lubricator very useful often as Magnesium Stearate, sodium lauryl sulphate and talcum powder.The weighting agent that the solids composition of similar type also can be used as gelatine capsule uses; Preferable material also comprises lactose (lactose) or lactose (milk sugar) and high-molecular weight polyoxyethylene glycol in this connection.When needing aqeous suspension and/or elixir for oral administration, described activeconstituents can be united with various sweeting agents or seasonings, tinting material or dyestuff, if desired, with the associating of emulsifying agent and/or suspension agent, and mix as water, ethanol, propylene glycol, glycerine or their various combining.
For parenteral admin (comprising intraperitoneal, subcutaneous, intravenously, intracutaneous or intramuscular injection), can adopt the solution of substituted tetracycline compound of the present invention in sesame oil or peanut oil or in aqueous solution of propylene glycol.If necessary, described aqueous solution buffering that should suit (preferred pH is greater than 8) and described liquid diluent at first are isoosmotic.These aqueous solution are suitable for intravenous purpose.Described oil solution is to be suitable for intraarticular, muscle and hypodermic purpose.Under aseptic condition, all these pharmaceutical solutionses are easy to finish by standard pharmaceutical technology well known to those skilled in the art.For parenteral application, the example of suitable formulations comprises solution, and the preferred oil solution or the aqueous solution and suspension, emulsion or implant comprise suppository.The tetracycline compound that replaces can for example be dispersed in it a kind of liquid vehicle with aseptic form, with many or single dose form preparation, and is for example general in stroke-physiological saline solution or 5% salt aqueous glucose solution that injection uses.
In addition, when treating the inflammatory diseases of skin, topical administration substituted tetracycline compound of the present invention also is possible.The example of local administration method comprises through skin, oral cavity or hypogloeeis to be used.For topical application, the treatment compound can be blended in the inertia topical carrier such as gel, ointment, washing lotion or emulsifiable paste on the pharmacology aptly.This type of topical carrier comprises water, glycerine, alcohol, propylene glycol, Fatty Alcohol(C12-C14 and C12-C18), triglyceride level, fatty acid ester or mineral oil.Other possible topical vehicle is Albolene, Wickenol 111, polyoxyethylene glycol, 95% ethanol, 5% Vinlub 73 in water, 5% sodium lauryl sulphate in water etc.In addition, if desired, also can add material such as antioxidant, wetting agent, viscosity stabilizer etc.
Use for enteron aisle, suitable especially is tablet, drageeing or the capsule with talcum powder and/or carbohydrate carrier tackiness agent etc., and carrier is preferably lactose and/or W-Gum and/or yam starch.Can use syrup, elixir etc., wherein increase sweet vehicle and be used.Can prepare slow releasing composition, comprise those compositions that activeconstituents is wherein for example protected by microencapsulation, multiple coatings etc. with special degradable dressing thing.
Except the treatment human patients, methods of treatment of the present invention also will have significant veterinary purpose, for example, be used for for example for example for example treatment of dog and cat of chicken, duck, goose, turkey etc., horse and pet of ox, sheep, goat, cow, pig etc., poultry of domestic animal.Compound of the present invention also can be used for treating non-animal patient, as plant.
The actual preferred amounts that should be appreciated that employed active compound in given therapy will be according to variations such as employed particular compound, the concrete composition of being prepared, use pattern, concrete medicine-feeding parts.The routine dose determination experiment that use is carried out according to aforementioned principle, those skilled in the art can be easy to definite best medicine-feeding rate to given medication.
Usually, can be with the dosage that before tsiklomitsin therapy is early used, uses, the The compounds of this invention that will be used for the treatment of gives the patient.For example, see the Physicians ' Desk Reference (clinicist's workbook).For example, the suitable effective dose of one or more The compounds of this invention will be in 0.01 to the 100 milligram/recipient scope of per kilogram of body weight/every day, preferably in the scope of recipient's per kilogram of body weight every day 0.1-50 milligram, more preferably in the scope of recipient's per kilogram of body weight every day 1-20 milligram.Required dosage is suitably and is administered once every day, or gives several sub-doses at interval or by other suitable timetable at one day appropriate time, for example 2-5 sub-doses.
Should be understood that also normal, conventional known preventive measure is usually directed to give tetracyclines, to guarantee their effectiveness under normal service condition.Especially when being used for the interior therapeutic of humans and animals, the doctor should take all reasonable precautions to avoid common known contraindication and toxic action.Therefore, in ordinary method, should consider the adverse effect that has recognized that usually fully, comprise the absorption damage of gi tract illness and inflammation, renal toxicity, anaphylaxis, blood variation and aluminium, calcium and magnesium ion.
Example of the present invention
Following examples are set forth the whole bag of tricks that synthesizes the tetracycline compound that replaces according to 9-of the present invention and 7-.Other compound of the present invention also can be used on this described method and/or methods known in the art are synthetic.Embodiment 1: the amino tetracycline compound that replaces of synthetic 9-
To Vibravenos (2g, 4.15mmol) add in the ice-cooled solution in the 30ml vitriol oil in batches saltpetre (0.5g, 1.2eq).Stirred this reaction mixture 11/2 hour.Then this acid solution is joined～the 200ml frozen water in.The yellow substance of filtering-depositing.This filtrate is dissolved in the methyl alcohol.Behind evaporation methyl alcohol, with this product of n-butanol extraction.Move down with saturated sodium bicarbonate twice of organic phase of washing and in vacuum and to desolvate.
Be dissolved among 50ml methyl alcohol and the dense HCl of 1ml the product that is produced and hydrogenation on Pd/C, obtain the amino Vibravenos positional isomers of 9-and 7-, be a kind of light yellow solid.Described isomer can be used HPLC and other technology purifying known in the art. The amino Vibravenos of 9-(9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin) MS (M+H): 460 1HNMR (CD 3OD): δ 7.62 (d, 1H, H-8), 7.14 (d, 1H, H-7), 4.42 (s, 1H, H-4), 3.6 (dd, 1H, H-5), 2.98,2.90 (each s, each 3H, Nme 2), 2.84 (d, 1H, H-4a), 2.72 (m, 1H, H-6), 2.59 (dd, 1H, H-5a), 1.51 (d, 3H, CH 3-C 6).The common of the mixing urea of 9-or 7-amino-6-α-tetracycline compound synthesized:
1.2 normal isocyanic ester are once joined 9-amino tetracycline compound in the solution of DMF and two normal diisopropyl ethyl amines.At room temperature stir this reaction mixture a few hours (common 4 hours to spending the night).Separate required product by the C18 reversed phase column chromatography.7-amino tetracycline compound urea can be used with 7-amino tetracycline compound synthetic as the similar approach of starting raw material.
In order to the following compound of top method preparation. Compd B: 9-amino naphthalenes base Vibravenos urea(1-naphthyl, 9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin mixing urea) 1HNMR (CD 3OD): δ 7.9 (d, 1H, H-8), 7.8-7.4 (m, 7H, aryl), 6.9 (bd, 1H, H-7), 4.42 (s, 1H, H-4), 3.6 (d, 1H, H-5), 2.88,2.77 (each s, each 3H, NMe 2), 2.84 (d, 1H, H-4a), 2.72 (m, 1H, H-6), 2.59 (dd, 1H, H-5a), 1.31 (d, 3H, CH 3-C 6).MS (M+H): calculated value, 629.63; Measured value, 629.16. Compd E: 9-aminophenyl Vibravenos urea(phenyl, 9-amino-α-deoxidation-5-hydroxyl-tsiklomitsin mixing urea) 1HNMR (CD 3OD): δ 8.25 (d, 1H, H-8), 7.45 (d, 2H, aryl), 7.29 (m, 2H, aryl), 7.0 (a, 1H, aryl), 6.9 (d, 1H, H-7), 4.25 (s, 1H, H-4), 3.6 (dd, 1H, H-5), 2.85 (bs, 6H, NMe 2), 2.84 (d, 1H, H-4a), 2.72 (m, 1H, H-6), 2.58 (dd, 1H, H-5a), 1.54 (d, 3H, CH 3-C 6).MS (M+H): calculated value, 579.57; Measured value, 579.15. Compound F 17-hydroxy-corticosterone: 9-amino-tertiary butyl Vibravenos urea(tertiary butyl, 9-amino-6-α-deoxidation-5-hydroxyl-tsiklomitsin mixing urea) 1HNMR (CD 3OD): δ 8.1 (d, 1H, H-8), 6.84 (d, 1H, H-7), 4.31 (s, 1H, H-4), 3.55 (dd, 1H, H-5), 2.91 (bs, 6H, NMe 2), 2.71-2.57 (m, 3H, H-4a, H-6, H-5a), 1.51 (d, 3H, CH 3-C 6), 1.36 (s, 9H, the tertiary butyls).MS (M+H): calculated value, 559.58; Measured value, 559.19. Compound I: 9-(4 '-chlorine, 2 '-trifluoromethyl amino)-Vibravenos urea4-chlorine, 2-trifluoromethyl, 9-amino-6-α-deoxidation-5-hydroxyl-tsiklomitsin mixing urea 1HNMR (CD 3OD): δ 8.28 (d, 1H, H-8), 7.89 (d, 1H, aryl), 7.66 (s, 1H, aryl), 7.58 (d, 1H, aryl), 6.93 (d, 1H, H-7), 4.42 (s, 1H, H-4), 3.56 (dd, 1H, H-5), 2.98 ﹠amp; 2.90 (each s, 3H, NMe 2), 2.84 (d, 2H, H-4a), 2.72 (m, 1H, H-6), 2.56 (dd, 1H, H-5a), 1.52 (d, 3H, CH 3-C 6).MS (M+H): calculate Compd A J:9-(3, two (trifluoromethyl) amino of 5-) Vibravenos ureaThe general of carbamate of (3,5-two (trifluoromethyl), 9-amino-6-α-deoxidation-5-hydroxyl-tsiklomitsin mixing urea) 9-or 7-amino-Vibravenos synthesized:
In the presence of two normal diisopropylethylamine, in the disposable DMF solution that joins the amino Vibravenos of 9-of 1.2 normal chloro-formic esters.At room temperature stir this reaction mixture a few hours.Separate required product by the C18 reversed phase column chromatography.7-amino tetracycline compound carbamate can be with synthesizing as the similar method of starting raw material with 7-amino tetracycline compound.With the synthetic following carbamate of above-described general synthetic method. The amino Vibravenos of compd A: FMOC-9-(N-fluorenyl methoxy carbonyl 9-amino-6-α-deoxidation-5-hydroxyl-tsiklomitsin) 1HNMR (CD 3OD): δ 7.9 (bd, 1H, H-8), 7.69 (d, 2H, aryl), 7.56 (m, 2H, aryl), 7.29 (m, 4H, aryl), 6.8 (d, 1H, H-7), 4.35 (d, 2H, CH 2), 4.30 (s, 1H, H-4), 4.15 (m, 1H, CH), 3.5 (dd, 1H, H-5), 2.85 (bd, 6H, NMe 2), 2.83 (d, 1H, H-4a), 2.73 (m, 1H, H-6a), 2.57 (dd, 1H, H-5a), 1.40 (d, 3H, CH 3-C 6).MS (M+H): calculate 682.69; Measured value, 682. Compound K: 9-(fluorophenyl) Vibravenos carbamate(N-is to fluorophenoxy carbonyl 9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin) 1HNMR (CD 3OD): δ 7.92 (d, 1H, H-8), 7.11-6.98 (m, 4H, aryl), 6.85 (d, 1H, H-7), 4.34 (s, 1H, H-4), 3.42 (dd, 1H, H-5), 2.86 (bd, 6H, NMe 2), 2.83 (d, 1H, H-5a), 2.72 (m, 1H, H-6), 2.56 (dd, 1H, H-5a), 1.43 (d, 3H, CH 3-C 6).MS (M+H): calculate 598.55; Measured value, 598.50. Compound L: 9-(4-p-methoxy-phenyl) Vibravenos carbamate(N-is to methoxyl group phenyloxycarbonyl 9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin) 1HNMR (CD 3OD): δ 7.92 (bd, 1H, H-8), 6.97 (d, 2H, aryl), 6.82 (m, 3H, H-7 and aryl), 4.36 (s, 1H, H-4), 3.66 (s, 3H, OMe), 3.4 (d, 1H, H-5), 2.86 (bd, 6H, NMe 2), 2.83 (d, 1H, H-4a), 2.78 (m, 1H, H-6), 2.56 (dd, 1H, H-5a), 1.43 (d, 3H, CH 3-C 6).MS (M+H): calculate 610.58; Measured value, 610.50. The amino Vibravenos of compound M:9-BOC-(N-tert-butoxycarbonyl 9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin) 1HNMR (CD 3OD): δ 8.04 (d, 1H, H-8), 6.92 (d, 1H, H-7), 4.05 (s, 1H, H-4), 3.62 (dd, 1H, H-5), 2.82 (bs, 6H, NMe 2), 2.83 (d, 1H, H-4a), 2.74 (m, 1H, H-6), 2.57 (dd, 1H, H-5a), 1.52 (bs, 12H, CH 3-C 6+ the tertiary butyl).MS (M+H): calculate 560.57; Measured value, 560.16. Compd A P:9-neo-pentyl Minocycline HCl carbamate(N-neo-pentyl oxygen base carbonyl 9-amino-6-α-deoxidation-5-hydroxyl-tsiklomitsin) 1HNMR (CD 3OD): δ 7.9 (d, 1H, H-8), 6.9 (d, 1H, H-7), 4.36 (s, 1H, H-4), 3.77 (s, 2H, neo-pentyl CH2), 3.6 (dd, 1H, H-5), 2.88,2.81 (bs, 6H, NMe 2), 2.84 (d, 1H, H-4a), 2.72 (m, 1H, H-6), 2.59 (dd, 1H, H-5a), 1.45 (d, 3H, CH 3-C 6), 0.89 (s, 9H, neo-pentyl CH 3).MS (M+H): calculate 587.63; Measured value, 587.5.The thiazolamine derivative of synthetic tetracycline compound
(1.80g 5mmol) is dissolved in the 10ml ethyl acetate with the fluorenyl methoxy carbonyl chloride.At 0 ℃, under the nitrogen pressure, this drips of solution is added in the suspension of thiocyanic ester (1.2eq) in the 10ml ethyl acetate.Stirring this reaction mixture spends the night.Filter this reaction mixture so that remove remaining salt through Celite pad then, and under vacuum, remove ethyl acetate.This rough yellow substance is used for synthetic following compound. The amino Vibravenos thioformamide of compd A T:9-FMOC-(3-(fluorenyl methoxy carbonyl)-1-(9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)-thioformamide)
In the presence of 227ul (2eq) diisopropylethylamine, the disposable fluorenyl methoxy-carbony isorhodanate that is added in the 182mg among the 1ml DMF in the amino Vibravenos of the 300mg in 3ml DMF (0.65mmol) 9-.At room temperature stirred this reaction mixture 5 hours.Separate required product by the C18 reversed phase column chromatography.
1HNMR (CD 3OD): δ 8.82 (d, 1H, H-8), 7.82 (d, 2H, aryl), 7.72 (d, 2H, aryl), 7.4 (m, 4H, aryl), 6.92 (d, 1H, H-7), 4.56 (d, 2H, CH 2), 4.44 (s, 1H, H-4), 4.30 (m, 1H, CH), 3.6 (dd, 1H, H-5), 2.98 (bd, 6H, NMe 2), 2.84 (d, 1H, H-4a), 2.73 (m, 1H, H-6), 2.56 (dd, 1H, H-5a), 1.54 (d, 3H, CH 3-C 6).MS (M+H): calculate 741.78; Measured value, 741.28. 6-α-deoxidation-5-hydroxyl-tsiklomitsin thiocarbamide
At room temperature, in the DMF of 2% piperidines, 2%DBU solution, 3-(fluorenyl methoxy carbonyl)-1-(9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)-thioformamide of 300mg (0.405mmol) is deblocked.This solvent of vaporising under vacuum after with dense HCl acidifying then.Resistates is dissolved among the 1ml MeOH and with it is added drop-wise in the 100ml cold ethyl acetate.The yellow solid of filtering-depositing is also dry. 1HNMR (CD 3OD): δ 7.90 (d, 1H, H-8), 6.95 (d, 1H, H-7), 4.48 (s, 1H, H-4), 3.57 (dd, 1H, H-5), 3.04,2.92 (two s, each 3H, NMe 2), 2.84 (d, 1H, H-4a), 2.7 (m, 1H, H-6), 2.6 (dd, 1H, H-5a), 1.54 (d, 3H, CH 3-C 6).MS (M+H): calculate 519.54; Measured value, 519.20.The general of 7-or 9-(2 '-thiazolyl amino) tetracycline compound synthesized
In the disposable tetracycline compound thiocarbamide that joins in the mixture of the diisopropylethylamine of DMF/ diox (3: 1) and monovalent of suitable α-bromoketone.Stirring this reaction mixture spends the night.Separate described thiazole product by the C18 reversed phase column chromatography.With the synthetic following thiazolium compounds of above-described method. Compound N: 9-(4 '-phenyl thiazole base)-amino Vibravenos2[9 (amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)]-the 4-phenyl thiazole: 1HNMR (CD 3OD): δ 8.25 (d, 1H, H-8), 7.8 (d, 2H, aryl), 7.45 (m, 3H, aryl), 7.1 (s, 1H, vinyl), 7.09 (d, 1H, H-7), 4.46 (s, 1H, H-4), 3.6 (dd, 1H, H-5), 2.91﹠amp; 2.88 (two s, each 3H, NMe 2), 2.84 (d, 1H, H-4a), 2.7 (m, 1H, H-6), 2.57 (dd, 1H, H-5a), 1.6 (d, 3H, CH 3-C 6).MS (M+H): calculate 619.66; Measured value, 619.19. Compound O:9-(4 '-ethyl thiazole base)-amino Vibravenos2[9-(amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)-4-ethyl] thiazole 1HNMR (CD 3OD): δ 7.9 (d, 1H, H-8), 7.05 (d, 1H, H-7), 6.55 (s, 1H, vinyl), 4.46 (s, 1H, H-4), 3.57 (dd, 1H, H-5a), 2.96 (bs, 6H, NMe 2), 2.87 (d, 1H, H-4a), 2.7 (m, 1H, H-6), 2.6 (m, 3H, the CH of H-5a and ethyl 2), 1.59 (d, 3H, CH 3-C 6), 1.28 (d, 3H, the CH of ethyl 3).MS (M+H): calculate 571.62; Measured value, 571.2. Compound Q: 9-(4-p-methoxy-phenyl thiazolyl)-amino Vibravenos(2[(9-amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)]-4-(4-p-methoxy-phenyl) thiazole) 1HNMR (CD 3OD): δ 7.94 (d, 1H, H-8), 7.68 (d, 2H, aryl), 7.10 (d, 1H, H-7), 7.06 (d, 2H, aryl), 4.49 (s, 1H, H-4), 3.86 (s, 3H, OMe), 3.56 (dd, 1H, H-5), 3.0 ﹠amp; 2.94 (two s, each 3H, NMe 2), 2.87 (d, 1H, H-4a), 2.73 (m, 1H, H-6), 1.63 (d, 3H, CH 3-C 6).MS (M+H): calculate 649.68; Measured value, 649.15. Compound R: 9-(3-nitrophenyl thiazolyl)-amino Vibravenos(2[9-(amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)]-4-(3-nitrophenyl) thiazole) 1HNMR (CD 3OD): δ 8.6 (m, 2H, aryl), 8.2 (d, 1H, H-8), 8.1 (d, 1H, aryl), 7.6 (m, 1H, aryl), 7.3 (s, 1H, vinyl), 6.9 (d, 1H, H-7), 4.44 (s, 1H, H-4), 3.57 (dd, 1H, H-5), 3.0 ﹠amp; 2.91 (two s, each 3H, NMe 2), 2.84 (s, 1H, H-4a), 2.7 (m, 1H, H-6), 2.57 (dd, 1H, H-5a), 1.56 (d, 3H, CH 3-C 6).MS (M+H): calculate 664.66; Measured value, 664.60. Compound S: 9-(4-methyl-5-phenyl thiazole base)-amino Vibravenos(2[9-(amino-6-α-deoxidation-5-hydroxyl tsiklomitsin)]-4-phenyl-5-methylthiazol) 1HNMR (CD 3OD): δ 7.98 (d, 1H, H-8), 7.6-7.4 (m, 5H, aryl), 7.05 (d, 1H, H-7), 4.46 (s, 1H, H-4), 3.57 (dd, 1H, H-5), 2.95 (bs, 6H,, NMe 2), 2.87 (d, 1H, H-4a), 2.7 (m, 1H, H-6), 2.6 (dd, 1H, H-5a), 2.36 (s, 3H, CH 3), 1.57 (d, 3H, CH 3-C 6).MS (M+H): calculate 633.68; Measured value, 633.61. Compound U:(9-(N, N-dimethylamino ethanoyl)-Vibravenos)With N, N-dimethylamino acetate (1.2mmol) is dissolved among the DMF (5ml) and adds O-benzotriazole-1-base-N, N, and N ', N '-tetramethyl-urea (uronium) hexafluorophosphate (HBTU, 1.2mmol).Then this solution of stirring at room 5 minutes.In this solution, add the amino Vibravenos (1mmol) of 9-, add subsequently diisopropylethylamine (DIEA, 1.2mmol).At room temperature stir this reaction 2 hours then.Under vacuum, remove this solvent, DMF.Should be dissolved among the 5ml MeOH also with automatic phial (autovials) filtration, with preparation property HPLC purifying by rough thing.The structure of this product 1H NMR, HPLC and MS characterization.Embodiment 2: external minimum inhibition concentration (MIC) is measured
Below measure and be used for determining that tetracycline compound suppresses the effect of common bacteria (intestinal bacteria, streptococcus aureus, E.hirae, enterococcus faecalis).With every kind of compound dissolution of 2mg in the DMSO of 100ul.Then this solution is joined in the Mueller Hinton meat soup (CAMHB) of positively charged ion-adjusting, the final concentration that makes compound is 200 μ g/ml.To the 50ul volume, the concentration of test-compound is 0.098 μ g/ml with this tetracycline compound solution dilution.Fresh logarithmic phase (log-phase) broth culture by strain subject carries out optical density(OD) (OD) mensuration.Dilute so that make final cell density be approximately 5 * 10 5CFU/ml.
The described cell suspending liquid of 50 μ l is joined in each hole of titer plate.Last cell density is approximately 5 * 10 5CFU/ml.In 35 ℃, ambient air incubator, cultivated these dull and stereotyped about 18 hours.
With a microplate read described flat board and when must the time estimate.MIC is defined as the minimum concentration of the tetracycline compound that suppresses growth.In table 2, *Expression suppresses good to a kind of concrete microbial growth, *Be illustrated in low concentration and suppress growth, and * *It is very good that expression suppresses growth.The tetracycline compound of some replacement of the present invention has the MIC ' s that is lower than about 10 μ g/ml.The tetracycline compound of other replacement of the present invention has the MIC ' s that is lower than about 5 μ g/ml, even other compound has the MIC ' s that is lower than about 1 μ g/ml.Equivalent
Those skilled in the art will recognize that or can only use normal experiment can determine the multiple Equivalent of concrete grammar described here.This type of Equivalent is considered to be within the purview and is covered by following claim.All reference, patent and the content that runs through the patent application that the application quotes are attached to herein by reference at this.For the present invention and embodiment thereof, can select suitable composition, technology and the method for those patents, application and other document.
Table 2
Figure A0181013200731
Figure A0181013200741
Figure A0181013200751
Figure A0181013200771
Figure A0181013200791
Figure A0181013200811
Figure A0181013200831
Figure A0181013200841

Claims (104)

1. the tetracycline compound of a replacement and pharmacy acceptable salt thereof, wherein said compound is a following formula:
Figure A0181013200021
Wherein
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, NR 9cC (=Z ') ZR 9aOr heteroaryl amino;
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 9dAnd R 9eCan be connected to form a ring;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 7dAnd R 7eCan be connected to form a ring;
Condition is to work as R 7At least R during for hydrogen or dialkyl amido 9One of be not hydrogen.
2. the compound of claim 1, wherein R 2, R 2 ', R 3, R 8, R 10, R 11And R 12Each is a hydrogen.
3. claim 1 or 2 compound, wherein R 4And R 4 'Each is an alkyl.
4. the compound of claim 3, wherein R 4And R 4 'Each is a methyl.
5. the compound of claim 4, wherein said compound is tsiklomitsin, Minocycline HCl, Sancycline, Vibravenos, duomycin, terramycin, Demethylchlortetracycline, or the derivative of metacycline.
6. any one compound, wherein R among the claim 1-5 5Be hydrogen.
7. the compound of claim 6, wherein X is CH 2, and R 7Be hydrogen.
8. the compound of claim 6, wherein X is CH 2, and R 7Be N (Me) 2
9. any one compound, wherein R among the claim 1-5 5Be hydroxyl or prodrug part, and X is CHR 6
10. the compound of claim 9, wherein R 5Be hydroxyl R 6Be methyl.
11. any one compound among the claim 1-10, wherein R 9Be NR 9cC (=Z ') ZR 9a
12. the compound of claim 11, wherein R 9cBe hydrogen.
13. the compound of claim 11 or 12, wherein Z ' is an oxygen.
14. any one compound among the claim 11-13, wherein Z is NR 9b
15. any one compound among the claim 11-13, wherein Z is an oxygen.
16. the compound of claim 11 or 12, wherein Z ' is a sulphur.
17. any one compound in the claim 11,12 or 16, wherein Z is NR 9b
18. any one compound in the claim 11,12 or 16, wherein Z is an oxygen.
19. any one compound among the claim 1-18, wherein R 9aBe selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl and polynary ring.
20. the compound of claim 19, wherein R 9aFor replace or unsubstituted alkyl.
21. the compound of claim 20, wherein R 9aReplaced by one or more substituting groups that are selected from alkoxy carbonyl, amino, aryl carbonyl, halogen, hydroxyl, alkylamino, alkoxyl group or aryl.
22. the compound of claim 20, wherein R 9aBe methyl, ethyl, the tertiary butyl, normal-butyl, isobutyl-or n-pentyl.
23. the compound of claim 21, wherein said alkyl is replaced by aromatic yl group.
24. the compound of claim 23, wherein said aromatic yl group are phenyl.
25. the compound of claim 21, wherein said alkyl is replaced by one or more halogens.
26. the compound of claim 24, wherein said halogen are bromine.
27. the compound of claim 19, wherein R 9aBe polynary ring.
28. the compound of claim 27, wherein R 9aBe the steroid base.
29. the compound of claim 28, wherein R 9aBe cholesterol.
30. the compound of claim 19, wherein R 9aBe that replace or unsubstituted aryl.
31. the compound of claim 30, aryl wherein said replacement or unsubstituted is a naphthyl.
32. the compound of claim 30, aryl wherein said replacement or unsubstituted has following formula:
33. the compound of claim 30, aryl wherein said replacement or unsubstituted is a phenyl.
34. the compound of claim 30 or 33, wherein said aryl is selected from following substituting group and replaces by one or more: alkyl, alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl, amido, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
35. the compound of claim 34, wherein said substituting group are alkyl.
36. the compound of claim 35, wherein said alkyl are unsubstituted.
37. the compound of claim 35, wherein said alkyl are methyl.
38. the compound of claim 35, wherein said alkyl is replaced by one or more halogens.
39. the compound of claim 34, wherein said substituting group are methoxyl group.
40. the compound of claim 34, wherein said substituting group is selected from alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl and amido.
41. any one compound among the claim 1-10, wherein R 9Be heteroaryl-amino.
42. the compound of claim 41, wherein said heteroaryl is that replace or unsubstituted thiazolyl.
43. the compound of claim 42, the thiazolyl of wherein said heteroaryl for replacing.
44. the compound of claim 43, the substituted or unsubstituted aryl of wherein said thiazolyl replaces.
45. the compound of claim 46, wherein said aryl are phenyl.
46. the compound of claim 44 or 45, wherein said aryl is selected from following substituting group and replaces by one or more: alkyl, alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, amido, trifluoromethyl, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
47. the compound of claim 46, wherein said substituting group are nitro.
48. the compound of claim 46, wherein said substituting group are alkyl.
49. the compound of claim 48, wherein said alkyl substituent are methyl.
50. the compound of claim 46, wherein said substituting group is selected from alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl and amido.
51. the compound of claim 50, wherein said dessert machine are alkoxy carbonyl.
52. the compound of claim 51, wherein said dessert machine are ethoxy carbonyl.
53. the compound of claim 1, wherein said compound is selected from:
Vibravenos 9-carboxylamine 9H-fluorenes-9-base methyl esters;
9-(naphthalene-1-yl) Vibravenos urea;
9-(3-methyl isophthalic acid-butyl) Vibravenos urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Vibravenos urea;
The amino Vibravenos of FMOC 9-;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos urea;
9-(4 '-fluorophenyl) Vibravenos carbamate;
9-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 9-BOC;
The amino Vibravenos of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(ethyl thiazole base);
(4-fluorophenyl thiazolyl) amino Vibravenos;
The amino Vibravenos of 9-(4 '-p-methoxy-phenyl thiazolyl);
The amino Vibravenos of 9-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Minocycline HCl carbamate;
The amino Sancycline of 9-(phenyl thiazole base);
The amino Vibravenos of 9-(adamantyl thiazolyl);
9-(naphthalene-1-base urea) Vibravenos 5-propionic ester;
Vibravenos 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
9-(naphthalene-1-yl) Vibravenos thiocarbamide;
9-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
9-phenyl Vibravenos thiocarbamide;
9-tertiary butyl Vibravenos thiocarbamide;
9-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
9-(4 '-fluorophenyl) Vibravenos thiocarbamate;
9-(4-p-methoxy-phenyl) Vibravenos thiocarbamate;
9-neo-pentyl Minocycline HCl thiocarbamate;
9-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
Minocycline HCl 9-carboxylamine 9H-fluorenes-9-base methyl esters;
9-(naphthalene-1-yl) Minocycline HCl urea;
9-(3-methyl isophthalic acid-butyl) Minocycline HCl urea;
9-phenyl Vibravenos urea;
9-tertiary butyl Minocycline HCl urea;
FMOC 9-amino minocycline ring element;
9-(4 '-chloro-2 '-trifluoromethyl) Minocycline HCl urea;
9-(4 '-fluorophenyl) Minocycline HCl carbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl carbamate;
9-BOC amino minocycline ring element;
9-(phenyl thiazole base) amino minocycline ring element;
9-(ethyl thiazole base) amino minocycline ring element;
(4 '-fluorophenyl thiazolyl) amino minocycline ring element;
9-(4 '-p-methoxy-phenyl thiazolyl) amino minocycline ring element;
9-9-(3 '-nitrophenyl thiazolyl) amino minocycline ring element;
The amino Vibravenos of 9-(4 '-methyl, 5 '-phenyl thiazole base);
9-neo-pentyl Vibravenos carbamate.
54. the compound of claim 1, wherein said compound is selected from:
9-(phenyl thiazole base) amino minocycline ring element;
9-(adamantyl thiazolyl) amino minocycline ring element;
Minocycline HCl 9-thiocarbamate 9H-fluorenes-9-base methyl esters;
9-(naphthalene-1-yl) Minocycline HCl thiocarbamide;
9-(3 '-methyl isophthalic acid-butyl) Minocycline HCl thiocarbamide;
9-phenyl Minocycline HCl thiocarbamide;
9-tertiary butyl Minocycline HCl thiocarbamide;
9-(4 '-fluorophenyl) Minocycline HCl thiocarbamate;
9-(4 '-p-methoxy-phenyl) Minocycline HCl thiocarbamate;
9-neo-pentyl Vibravenos thiocarbamate;
9-(2 '-bromotrifluoromethane) Vibravenos carbamate;
9-(n-pentyl) Minocycline HCl carbamate;
The amino Vibravenos of 9-(4 '-benzoyl benzoyl);
The amino Sancycline of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 9-(3 '-ethoxy carbonyl thiazolyl);
7-(4 '-aminomethyl phenyl) Sancycline carbamate;
9-(4 '-Trifluoromethoxyphen-l) Minocycline HCl urea;
9-(3 ', 5 '-two perfluorophenyls) Minocycline HCl thiocarbamide;
9-third-2 '-thiazolinyl Minocycline HCl carbamate;
9-(4 '-chlorine, 2 '-nitrophenyl) Minocycline HCl urea;
9-ethyl Minocycline HCl carbamate;
9-normal-butyl Minocycline HCl carbamate;
The positive fourth of 9--3-thiazolinyl Minocycline HCl carbamate;
9-isobutyl-Minocycline HCl carbamate,
And pharmacy acceptable salt and prodrug.
55. the compound of claim 1, wherein said compound is selected from:
Figure A0181013200101
56. any one compound among claim 1-6 and the 9-53, wherein R 7Be NR 7cC (=W ') WR 7a
57. the compound of claim 56, wherein R 9Be hydrogen.
58. the compound of claim 56 or 57, wherein R 7cBe hydrogen.
59. any one compound among the claim 56-58, wherein W ' is an oxygen.
60. any one compound among the claim 56-58, wherein W ' is a sulphur.
61. any one compound among the claim 56-60, wherein W is NR 7b
62. any one compound among the claim 56-60, wherein W is an oxygen.
63. any one compound among the claim 56-62, wherein R 7aBe selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl and polynary ring.
64. the compound of claim 63, wherein R 7aFor replace or unsubstituted alkyl.
65. the compound of claim 64, wherein said alkyl is replaced by aromatic yl group.
66. the compound of claim 63, aryl wherein said replacement or unsubstituted is a phenyl.
67. the compound of claim 65 or 66, wherein said aryl is selected from following substituting group and replaces by one or more: alkyl, alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aryloxycarbonyl, amido, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
68. the compound of claim 67, wherein said dessert machine are alkyl, alkoxyl group or nitro.
69. any one compound among claim 1-6 and the 9-52, wherein R 7Be heteroaryl-amino.
70. the compound of claim 69, wherein R 9Be hydrogen.
71. the compound of claim 69 or 70, wherein said heteroaryl is that replace or unsubstituted thiazolyl.
72. the compound of claim 71, the substituted or unsubstituted aryl of wherein said thiazolyl replaces.
73. the compound of claim 72, wherein said aryl are phenyl.
74. the compound of claim 73, wherein said aryl is selected from following substituting group and replaces by one or more: alkyl, alkenyl, alkynyl, aryl, alkoxyl group, aryloxy, alkyl-carbonyl, aryl carbonyl, amido, trifluoromethyl, halogen, nitro, azo-group, alkyl sulphonyl and aryl sulfonyl.
75. the compound of claim 74, wherein said substituting group are nitro.
76. the compound of claim 1, wherein said compound is selected from:
Vibravenos 7-carboxylamine 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos urea;
7-(3-methyl isophthalic acid-butyl) Vibravenos urea;
7-phenyl Vibravenos urea;
7-tertiary butyl Vibravenos urea;
The amino Vibravenos of 7-Fmoc;
7-(4 '-chloro-2-trifluoromethyl) Vibravenos urea;
7-(4 '-fluorophenyl) Vibravenos carbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos carbamate;
The amino Vibravenos of 7-BOC;
The amino Vibravenos of 7-(3 '-phenyl thiazole base);
The amino Vibravenos of 7-(3 '-ethyl thiazole base);
7-(4 "-the fluorophenyl thiazolyl) amino Vibravenos;
7-(4 "-the p-methoxy-phenyl thiazolyl) amino Vibravenos;
7-(phenyl thiazole base amino)-Sancycline;
The amino Vibravenos of 7-(3 '-nitrophenyl thiazolyl);
The amino Vibravenos of 7-(4 '-methyl, 5 '-phenyl thiazole base);
The amino Vibravenos of 7-(adamantyl thiazolyl);
Vibravenos 7-thiocarbamate 7H-fluorenes-7-base methyl esters;
7-(naphthalene-1-yl) Vibravenos thiocarbamide;
7-(3-methyl isophthalic acid-butyl) Vibravenos thiocarbamide;
7-phenyl amino Vibravenos thiocarbamide;
The amino Vibravenos thiocarbamide of the 7-tertiary butyl;
7-(4 '-chloro-2 '-trifluoromethyl) Vibravenos thiocarbamide;
7-(4 '-fluorophenyl) Vibravenos thiocarbamate;
7-(4 '-p-methoxy-phenyl) Vibravenos thiocarbamate;
7-(naphthalene-1-yl) Vibravenos urea 5-propionic ester;
7-(naphthalene-1-yl) Vibravenos thiocarbamide 5-propionic ester;
And pharmacy acceptable salt.
77. the method for the reactive disorder state of the mammiferous tsiklomitsin of treatment, this method comprises the tetracycline compound and the pharmacy acceptable salt thereof of the replacement that gives described Mammals formula (I):
Figure A0181013200131
Wherein
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, NR 9cC (=Z ') ZR 9aOr heteroaryl amino;
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 9dAnd R 9eCan be connected to form a ring;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 7dAnd R 7eCan be connected to form a ring;
Condition is to work as R 7R during for hydrogen or dialkyl amido 9Be not hydrogen.
78. the method for claim 77, wherein said tetracycline compound are compound any among the claim 1-76.
79. the method for claim 77 or 78, the reactive disorder state of wherein said tsiklomitsin is an infectation of bacteria.
80. the method for claim 79, wherein said infectation of bacteria is relevant with intestinal bacteria, streptococcus aureus, enterococcus faecalis or E.hirae.
81. the method for claim 79 or 80, wherein said infectation of bacteria has resistance to unsubstituted tetracycline compound.
82. the method for claim 77 or 78, wherein said tetracycline compound gives with a kind of pharmaceutically acceptable carrier.
83. a medicinal compositions, said composition comprise the substituted tetracycline compound and the pharmaceutically acceptable carrier for the treatment of significant quantity, the tetracycline compound and the pharmacy acceptable salt thereof of wherein said replacement have following formula: Wherein
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, NR 9cC (=Z ') ZR 9aOr heteroaryl amino;
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 9dAnd R 9eCan be connected to form a ring;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist; or the prodrug part, and R 7dAnd R 7eCan be connected to form a ring;
Condition is to work as R 7R during for dialkyl amido or hydrogen 9Be not hydrogen.
84. the medicinal compositions of claim 83, the tetracycline compound of wherein said replacement are compound any among the claim 1-76.
85. the medicinal compositions of claim 83 or 84, wherein said treatment significant quantity is effective to treatment or prevention infectation of bacteria.
86. the method for the tetracycline compound that synthetic 7-or 9-replace, this method comprises:
Under the condition that forms the nitrocycline compound, tetracycline compound is contacted with nitrating agent;
Under the condition that forms the amino tetracycline compound, this nitrocycline compound is contacted with hydrogenant agent; With
The amino tetracycline compound is contacted, so that form the tetracycline compound of 9-or 7-replacement with the amino-reactive substrate.
87. being 9-, the method for claim 86, the tetracycline compound of wherein said replacement replace.
88. being 7-, the method for claim 86, the tetracycline compound of wherein said replacement replace.
89. the method for claim 86, nitrating agent wherein are NaNO 2
90. the method for claim 86, wherein said nitrating agent contacts under acidic conditions with tetracycline compound.
91. the method for claim 86, wherein said hydrogenant agent are hydrogen.
92. the method for claim 91, wherein said hydrogenant agent further comprises transition-metal catalyst.
93. the method for claim 92, wherein said catalyzer are platinum.
94. the method for claim 86, wherein said amino-reactive compound is an isocyanic ester.
95. the method for claim 86, wherein said amino-reactive compound is a lsothiocyanates.
96. the method for claim 86, wherein said amino-reactive compound are chloro-formic ester unsubstituted or that replace.
97. the method for the tetracycline compound that the 7-of a synthesis type (I) or 9-replace, this method is included in reactive intermediate is contacted with suitable reagent, so that form the tetracycline compound that replaces, its Chinese style (I) is: Wherein
X is CHC (R 13Y ' Y), CR 6 'R 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6, R 6 'And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl or halogen;
R 7Be hydrogen, dialkyl amido, heteroaryl amino or NR 7cC (=W ') WR 7a
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, NR 9cC (=Z ') ZR 9aOr heteroaryl amino;
Z is CR 9dR 9e, NR 9bOr O;
Z ' is O or S;
R 9a, R 9b, R 9c, R 9dAnd R 9eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist, or the prodrug part;
W is CR 7dR 7e, NR 7bOr O;
W ' is O or S; And
R 7a, R 7b, R 7c, R 7dAnd R 7eEach is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, aryl sulfonyl, alkoxy carbonyl, aryl carbonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl independently, does not exist, or the prodrug part;
And pharmacy acceptable salt, condition is to work as R 7R during for dialkyl amido or hydrogen 9Be not hydrogen.
98. the method for claim 97, wherein said reactive intermediate are 7-or 9-diazonium salt.
99. the method for claim 97, wherein said reactive intermediate are 7-or 9-nitro-compound.
100. the method for claim 97, wherein said reactive intermediate are 7-or 9-thiocarbamide.
101. the method for claim 97, wherein said reactive intermediate are 7-or 9-thioformamide.
102. a reactive intermediate, wherein said reactive intermediate and pharmacy acceptable salt thereof have following formula: Wherein
X is CHC (R 13Y ' Y), CHR 6, S, NR 6Or O;
R 2Be hydrogen, alkyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 4And R 4 'Each is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino, aralkyl, aryl, heterocyclic radical, heteroaryl or prodrug part;
R 2 ', R 3, R 10, R 11And R 12Each is hydrogen or prodrug part;
R 5Be hydrogen, hydroxyl or prodrug part;
R 6And R 8Each independently is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
R 13Be hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl;
Each independently is hydrogen, halogen, hydroxyl, cyano group, sulfydryl, amino, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylamino or aralkyl for Y ' and Y;
R 9Be hydrogen, thiocarbamide, diazonium salt, thiocarboxamide or nitro;
R 7Be hydrogen, dialkyl amido, thiocarbamide, diazonium salt, thiocarboxamide or nitro;
Regulation is worked as R 7R during for dialkyl amido or hydrogen 9Be not hydrogen.
103. the reactive intermediate of claim 102, wherein R 7Be hydrogen, and R 9Be thiocarbamide, diazonium salt, thiocarboxamide or nitryl group.
104. the reactive intermediate of claim 102, wherein R 9Be hydrogen, and R 7Be thiocarbamide, diazonium salt, thiocarboxamide or nitryl group.
CN01810132A 2000-03-31 2001-03-30 7-and 9-carbamate, urea, thiourea, thiocarbamate and heteroaryl-amino substituted tetracycline compounds Pending CN1430600A (en)

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CN101759598B (en) * 2008-09-12 2011-11-09 山东轩竹医药科技有限公司 Tetracycline compound with amino acid amidine
CN101684083B (en) * 2008-09-16 2011-10-05 山东轩竹医药科技有限公司 Guanidinoalkanoylamino substituted tetracycline derivatives
CN101684080B (en) * 2008-09-16 2011-12-14 山东轩竹医药科技有限公司 Tetracycline compounds containing hydrazo
CN101759599B (en) * 2008-09-17 2012-05-30 山东轩竹医药科技有限公司 Tetracycline compound with amino oxime group
CN115551827A (en) * 2020-05-13 2022-12-30 卢内拉生物技术有限公司 9-amino-doxycycline myristoyl derivatives targeting cancer stem cells and preventing metastasis

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